References

1. Ceylan, C.; Hamacı, A.; Ayata, H.; Berberoglu, K.; Kılıç, A.; Güden, M.; Engin, K. Re-Irradiation of Locoregional NSCLC Recurrence Using Robotic Stereotactic Body Radiotherapy. Oncol. Res. Treat. 2017, 40, 207–214.
2. Formenti, S.C.; Demaria, S. Combining radiotherapy and cancer immunotherapy: A paradigm shift. J. Natl. Cancer Inst. 2013, 105, 256–265.
3. Kim, J.E.; Patel, M.A.; Mangraviti, A.; Kim, E.S.; Theodros, D.; Velarde, E.; Liu, A.; Sankey, E.W.; Tam, A.; Xu, H.; et al. Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas. Clin. Cancer Res. 2017, 23, 124–136.
4. Dovedi, S.J.; Lipowska-Bhalla, G.; Beers, S.A.; Cheadle, E.J.; Mu, L.; Glennie, M.J.; Illidge, T.M.; Honeychurch, J. Antitumor Efficacy of Radiation plus Immunotherapy Depends upon Dendritic Cell Activation of Effector CD8+ T Cells. Cancer Immunol. Res. 2016, 4, 621–630.
5. Herrera, F.G.; Irving, M.; Kandalaft, L.E.; Coukos, G. Rational combinations of immunotherapy with radiotherapy in ovarian cancer. Lancet Oncol. 2019, 20, e417–e433.
6. Sharabi, A.B.; Lim, M.; DeWeese, T.L.; Drake, C.G. Radiation and checkpoint blockade immunotherapy: Radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015, 16, e498–e509.
7. Dokic, I.; Niklas, M.; Zimmermann, F.; Mairani, A.; Seidel, P.; Krunic, D.; Jakel, O.; Debus, J.; Greilich, S.; Abdollahi, A. Correlation of Particle Traversals with Clonogenic Survival Using Cell-Fluorescent Ion Track Hybrid Detector. Front. Oncol. 2015, 5, 275.
8. Niklas, M.; Greilich, S.; Melzig, C.; Akselrod, M.S.; Debus, J.; Jakel, O.; Abdollahi, A. Engineering cell-fluorescent ion track hybrid detectors. Radiat. Oncol. 2013, 8, 141.
9. Walsh, D.W.M.; Liew, H.; Schlegel, J.; Mairani, A.; Abdollahi, A.; Niklas, M. Carbon ion dosimetry on a fluorescent nuclear track detector using widefield microscopy. Phys. Med. Biol. 2020, 65, 21NT02.
10. Pantelias, A.; Zafiropoulos, D.; Cherubini, R.; Sarchiapone, L.; De Nadal, V.; Pantelias, G.E.; Georgakilas, A.G.; Terzoudi, G.I. Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering-A Critical Risk for Chromothripsis. Cancers 2020, 12, 2336.
11. Dokic, I.; Mairani, A.; Niklas, M.; Zimmermann, F.; Chaudhri, N.; Krunic, D.; Tessonnier, T.; Ferrari, A.; Parodi, K.; Jakel, O.; et al. Next generation multi-scale biophysical characterization of high precision cancer particle radiotherapy using clinical proton, helium-, carbon- and oxygen ion beams. Oncotarget 2016, 7, 56676–56689.
12. Garnett, C.T.; Palena, C.; Chakraborty, M.; Tsang, K.Y.; Schlom, J.; Hodge, J.W. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res. 2004, 64, 7985–7994.
13. Dovedi, S.J.; Cheadle, E.J.; Popple, A.L.; Poon, E.; Morrow, M.; Stewart, R.; Yusko, E.C.; Sanders, C.M.; Vignali, M.; Emerson, R.O.; et al. Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade. Clin. Cancer Res. 2017, 23, 5514–5526.
14. Aliru, M.L.; Schoenhals, J.E.; Venkatesulu, B.P.; Anderson, C.C.; Barsoumian, H.B.; Younes, A.I.; Lakshmi, S.K.M.; Soeung, M.; Aziz, K.E.; Welsh, J.W.; et al. Radiation therapy and immunotherapy: What is the optimal timing or sequencing? Immunotherapy 2018, 10, 299–316.
15. Emens, L.A.; Ascierto, P.A.; Darcy, P.K.; Demaria, S.; Eggermont, A.M.M.; Redmond, W.L.; Seliger, B.; Marincola, F.M. Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. Eur. J. Cancer 2017, 81, 116–129.
16. Wilkins, R.C.; Wilkinson, D.; Maharaj, H.P.; Bellier, P.V.; Cybulski, M.B.; McLean, J.R.N. Differential apoptotic response to ionizing radiation in subpopulations of human white blood cells. Mutat. Res. /Genet. Toxicol. Environ. Mutagenesis 2002, 513, 27–36.
17. Vanpouille-Box, C.; Diamond, J.M.; Pilones, K.A.; Zavadil, J.; Babb, J.S.; Formenti, S.C.; Barcellos-Hoff, M.H.; Demaria, S. TGFβ Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity. Cancer Res. 2015, 75, 2232–2242.
18. Rodríguez-Ruiz, M.E.; Rodríguez, I.; Mayorga, L.; Labiano, T.; Barbes, B.; Etxeberria, I.; Ponz-Sarvise, M.; Azpilikueta, A.; Bolaños, E.; Sanmamed, M.F.; et al. TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies. Mol. Cancer Ther. 2019, 18, 621–631.
19. Gong, J.; Le, T.Q.; Massarelli, E.; Hendifar, A.E.; Tuli, R. Radiation therapy and PD-1/PD-L1 blockade: The clinical development of an evolving anticancer combination. J. Immunother. Cancer 2018, 6, 46.
20. Di Maggio, F.M.; Minafra, L.; Forte, G.I.; Cammarata, F.P.; Lio, D.; Messa, C.; Gilardi, M.C.; Bravatà, V. Portrait of inflammatory response to ionizing radiation treatment. J. Inflamm. 2015, 12, 14.
21. Schaue, D.; Kachikwu, E.L.; McBride, W.H. Cytokines in radiobiological responses: A review. Radiat. Res. 2012, 178, 505–523.
22. Gupta, A.; Probst, H.C.; Vuong, V.; Landshammer, A.; Muth, S.; Yagita, H.; Schwendener, R.; Pruschy, M.; Knuth, A.; van den Broek, M. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J. Immunol. 2012, 189, 558–566.
23. Goldszmid, R.S.; Idoyaga, J.; Bravo, A.I.; Steinman, R.; Mordoh, J.; Wainstok, R. Dendritic cells charged with apoptotic tumor cells induce long-lived protective CD4+ and CD8+ T cell immunity against B16 melanoma. J. Immunol. 2003, 171, 5940–5947.
24. Malynn, B.A.; Romeo, D.T.; Wortis, H.H. Antigen-specific B cells efficiently present low doses of antigen for induction of T cell proliferation. J. Immunol. 1985, 135, 980–988.
25. Burnette, B.C.; Liang, H.; Lee, Y.; Chlewicki, L.; Khodarev, N.N.; Weichselbaum, R.R.; Fu, Y.-X.; Auh, S.L. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 2011, 71, 2488–2496.
26. Hellevik, T.; Pettersen, I.; Berg, V.; Winberg, J.O.; Moe, B.T.; Bartnes, K.; Paulssen, R.H.; Busund, L.T.; Bremnes, R.; Chalmers, A.; et al. Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced. Radiat. Oncol. 2012, 7, 59.
27. McLaughlin, M.; Patin, E.C.; Pedersen, M.; Wilkins, A.; Dillon, M.T.; Melcher, A.A.; Harrington, K.J. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer 2020, 20, 203–217.
28. Pitt, J.M.; Marabelle, A.; Eggermont, A.; Soria, J.C.; Kroemer, G.; Zitvogel, L. Targeting the tumor microenvironment: Removing obstruction to anticancer immune responses and immunotherapy. Ann. Oncol. 2016, 27, 1482–1492.
29. Blonska, M.; Agarwal, N.K.; Vega, F. Shaping of the tumor microenvironment: Stromal cells and vessels. Semin. Cancer Biol. 2015, 34, 3–13.
30. Liu, Y.; Dong, Y.; Kong, L.; Shi, F.; Zhu, H.; Yu, J. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J. Hematol. Oncol. 2018, 11, 104.
31. Gómez, V.; Mustapha, R.; Ng, K.; Ng, T. Radiation therapy and the innate immune response: Clinical implications for immunotherapy approaches. Br. J. Clin. Pharmacol. 2020, 86, 1726–1735.
32. Balkwill, F.R.; Capasso, M.; Hagemann, T. The tumor microenvironment at a glance. J. Cell Sci. 2012, 125, 5591–5596.
33. Dewey, W.C.; Ling, C.C.; Meyn, R.E. Radiation-induced apoptosis: Relevance to radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 1995, 33, 781–796.
34. Wu, Q.; Allouch, A.; Martins, I.; Brenner, C.; Modjtahedi, N.; Deutsch, E.; Perfettini, J.-L. Modulating Both Tumor Cell Death and Innate Immunity Is Essential for Improving Radiation Therapy Effectiveness. Front. Immunol. 2017, 8, 613.
35. Eriksson, D.; Stigbrand, T. Radiation-induced cell death mechanisms. Tumour Biol. 2010, 31, 363–372.
36. Chen, J.; Harding, S.M.; Natesan, R.; Tian, L.; Benci, J.L.; Li, W.; Minn, A.J.; Asangani, I.A.; Greenberg, R.A. Cell Cycle Checkpoints Cooperate to Suppress DNA- and RNA-Associated Molecular Pattern Recognition and Anti-Tumor Immune Responses. Cell Rep. 2020, 32, 108080.
37. Sachet, M.; Liang, Y.Y.; Oehler, R. The immune response to secondary necrotic cells. Apoptosis 2017, 22, 1189–1204.
38. Sia, J.; Szmyd, R.; Hau, E.; Gee, H.E. Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer. Front. Cell Dev. Biol. 2020, 8, 41.
39. Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.; Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.; et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018, 25, 486–541.
40. Kepp, O.; Senovilla, L.; Vitale, I.; Vacchelli, E.; Adjemian, S.; Agostinis, P.; Apetoh, L.; Aranda, F.; Barnaba, V.; Bloy, N.; et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 2014, 3, e955691.
41. Galluzzi, L.; Vitale, I.; Warren, S.; Adjemian, S.; Agostinis, P.; Martinez, A.B.; Chan, T.A.; Coukos, G.; Demaria, S.; Deutsch, E.; et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J. Immunother. Cancer 2020, 8.
42. Garg, A.D.; Galluzzi, L.; Apetoh, L.; Baert, T.; Birge, R.B.; Bravo-San Pedro, J.M.; Breckpot, K.; Brough, D.; Chaurio, R.; Cirone, M.; et al. Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death. Front. Immunol. 2015, 6, 588.
43. Zappasodi, R.; Pupa, S.M.; Ghedini, G.C.; Bongarzone, I.; Magni, M.; Cabras, A.D.; Colombo, M.P.; Carlo-Stella, C.; Gianni, A.M.; Di Nicola, M. Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death. Cancer Res. 2010, 70, 9062–9072.
44. Walle, T.; Martinez Monge, R.; Cerwenka, A.; Ajona, D.; Melero, I.; Lecanda, F. Radiation effects on antitumor immune responses: Current perspectives and challenges. Ther. Adv. Med. Oncol. 2018, 10, 1758834017742575.
45. Gameiro, S.R.; Jammeh, M.L.; Wattenberg, M.M.; Tsang, K.Y.; Ferrone, S.; Hodge, J.W. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 2014, 5, 403–416.
46. Golden, E.B.; Frances, D.; Pellicciotta, I.; Demaria, S.; Helen Barcellos-Hoff, M.; Formenti, S.C. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 2014, 3, e28518.
47. Rubner, Y.; Muth, C.; Strnad, A.; Derer, A.; Sieber, R.; Buslei, R.; Frey, B.; Fietkau, R.; Gaipl, U.S. Fractionated radiotherapy is the main stimulus for the induction of cell death and of Hsp70 release of p53 mutated glioblastoma cell lines. Radiat. Oncol. 2014, 9, 89.
48. Bains, S.J.; Abrahamsson, H.; Flatmark, K.; Dueland, S.; Hole, K.H.; Seierstad, T.; Redalen, K.R.; Meltzer, S.; Ree, A.H. Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer. Cancer Immunol. Immunother. 2020, 69, 355–364.
49. Suzuki, Y.; Mimura, K.; Yoshimoto, Y.; Watanabe, M.; Ohkubo, Y.; Izawa, S.; Murata, K.; Fujii, H.; Nakano, T.; Kono, K. Immunogenic Tumor Cell Death Induced by Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma. Cancer Res. 2012, 72, 3967.
50. Gorchs, L.; Hellevik, T.; Bruun, J.A.; Camilio, K.A.; Al-Saad, S.; Stuge, T.B.; Martinez-Zubiaurre, I. Cancer-associated fibroblasts from lung tumors maintain their immunosuppressive abilities after high-dose irradiation. Front. Oncol. 2015, 5, 87.
51. Lhuillier, C.; Rudqvist, N.P.; Elemento, O.; Formenti, S.C.; Demaria, S. Radiation therapy and anti-tumor immunity: Exposing immunogenic mutations to the immune system. Genome Med. 2019, 11, 40.
52. Spiotto, M.; Fu, Y.X.; Weichselbaum, R.R. The intersection of radiotherapy and immunotherapy: Mechanisms and clinical implications. Sci. Immunol. 2016, 1.
53. Garrido, F.; Romero, I.; Aptsiauri, N.; Garcia-Lora, A.M. Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype. Int. J. Cancer 2016, 138, 271–280.
54. Dillon, M.T.; Bergerhoff, K.F.; Pedersen, M.; Whittock, H.; Crespo-Rodriguez, E.; Patin, E.C.; Pearson, A.; Smith, H.G.; Paget, J.T.E.; Patel, R.R.; et al. ATR Inhibition Potentiates the Radiation-induced Inflammatory Tumor Microenvironment. Clin. Cancer Res. 2019, 25, 3392–3403.
55. Reits, E.A.; Hodge, J.W.; Herberts, C.A.; Groothuis, T.A.; Chakraborty, M.; Wansley, E.K.; Camphausen, K.; Luiten, R.M.; de Ru, A.H.; Neijssen, J.; et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 2006, 203, 1259–1271.
56. Lin, W.; Xu, Y.; Chen, X.; Liu, J.; Weng, Y.; Zhuang, Q.; Lin, F.; Huang, Z.; Wu, S.; Ding, J.; et al. Radiation-induced small extracellular vesicles as “carriages” promote tumor antigen release and trigger antitumor immunity. Theranostics 2020, 10, 4871–4884.
57. Arnold, K.M.; Flynn, N.J.; Raben, A.; Romak, L.; Yu, Y.; Dicker, A.P.; Mourtada, F.; Sims-Mourtada, J. The Impact of Radiation on the Tumor Microenvironment: Effect of Dose and Fractionation Schedules. Cancer Growth Metastasis 2018, 11, 1179064418761639.
58. Lambin, P.; Lieverse, R.I.Y.; Eckert, F.; Marcus, D.; Oberije, C.; van der Wiel, A.M.A.; Guha, C.; Dubois, L.J.; Deasy, J.O. Lymphocyte-Sparing Radiotherapy: The Rationale for Protecting Lymphocyte-rich Organs When Combining Radiotherapy With Immunotherapy. Semin. Radiat. Oncol. 2020, 30, 187–193.
59. Davuluri, R.; Jiang, W.; Fang, P.; Xu, C.; Komaki, R.; Gomez, D.R.; Welsh, J.; Cox, J.D.; Crane, C.H.; Hsu, C.C.; et al. Lymphocyte Nadir and Esophageal Cancer Survival Outcomes After Chemoradiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 2017, 99, 128–135.
60. Falcke, S.E.; Rühle, P.F.; Deloch, L.; Fietkau, R.; Frey, B.; Gaipl, U.S. Clinically Relevant Radiation Exposure Differentially Impacts Forms of Cell Death in Human Cells of the Innate and Adaptive Immune System. Int. J. Mol. Sci. 2018, 19, 3574.
61. Liang, H.; Deng, L.; Hou, Y.; Meng, X.; Huang, X.; Rao, E.; Zheng, W.; Mauceri, H.; Mack, M.; Xu, M.; et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 2017, 8, 1736.
62. Heylmann, D.; Ponath, V.; Kindler, T.; Kaina, B. Comparison of DNA repair and radiosensitivity of different blood cell populations. Sci. Rep. 2021, 11, 2478.
63. Conrad, S.; Ritter, S.; Fournier, C.; Nixdorff, K. Differential Effects of Irradiation with Carbon Ions and X-Rays on Macrophage Function. J. Radiat. Res. 2009, 50, 223–231.
64. Arina, A.; Beckett, M.; Fernandez, C.; Zheng, W.; Pitroda, S.; Chmura, S.J.; Luke, J.J.; Forde, M.; Hou, Y.; Burnette, B.; et al. Tumor-reprogrammed resident T cells resist radiation to control tumors. Nat. Commun. 2019, 10, 3959.
65. Galon, J.; Angell, H.K.; Bedognetti, D.; Marincola, F.M. The continuum of cancer immunosurveillance: Prognostic, predictive, and mechanistic signatures. Immunity 2013, 39, 11–26.
66. Merrick, A.; Errington, F.; Milward, K.; O’Donnell, D.; Harrington, K.; Bateman, A.; Pandha, H.; Vile, R.; Morrison, E.; Selby, P.; et al. Immunosuppressive effects of radiation on human dendritic cells: Reduced IL-12 production on activation and impairment of naive T-cell priming. Br. J. Cancer 2005, 92, 1450–1458.
67. Heylmann, D.; Badura, J.; Becker, H.; Fahrer, J.; Kaina, B. Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: Key role of ATM in the differential radiation response. Cell Death Dis. 2018, 9, 1053.
68. Frey, B.; Rückert, M.; Weber, J.; Mayr, X.; Derer, A.; Lotter, M.; Bert, C.; Rödel, F.; Fietkau, R.; Gaipl, U.S. Hypofractionated Irradiation Has Immune Stimulatory Potential and Induces a Timely Restricted Infiltration of Immune Cells in Colon Cancer Tumors. Front. Immunol. 2017, 8, 231.
69. Martinez-Zubiaurre, I.; Chalmers, A.J.; Hellevik, T. Radiation-Induced Transformation of Immunoregulatory Networks in the Tumor Stroma. Front. Immunol. 2018, 9, 1679.
70. Sun, G.-Y.; Wang, S.-L.; Song, Y.-W.; Jin, J.; Wang, W.-H.; Liu, Y.-P.; Ren, H.; Fang, H.; Tang, Y.; Zhao, X.-R.; et al. Radiation-Induced Lymphopenia Predicts Poorer Prognosis in Patients With Breast Cancer: A Post Hoc Analysis of a Randomized Controlled Trial of Postmastectomy Hypofractionated Radiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 2020, 108, 277–285.
71. Genard, G.; Lucas, S.; Michiels, C. Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies. Front. Immunol. 2017, 8, 828.
72. Chiang, C.S.; Fu, S.Y.; Wang, S.C.; Yu, C.F.; Chen, F.H.; Lin, C.M.; Hong, J.H. Irradiation promotes an m2 macrophage phenotype in tumor hypoxia. Front. Oncol. 2012, 2, 89.
73. Park, H.J.; Griffin, R.J.; Hui, S.; Levitt, S.H.; Song, C.W. Radiation-induced vascular damage in tumors: Implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat. Res. 2012, 177, 311–327.
74. Barker, H.E.; Paget, J.T.E.; Khan, A.A.; Harrington, K.J. The tumour microenvironment after radiotherapy: Mechanisms of resistance and recurrence. Nat. Rev. Cancer 2015, 15, 409–425.
75. Lugade, A.A.; Moran, J.P.; Gerber, S.A.; Rose, R.C.; Frelinger, J.G.; Lord, E.M. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol. 2005, 174, 7516–7523.
76. Wood, J.; Yasmin-Karim, S.; Mueller, R.; Viswanathan, A.N.; Ngwa, W. Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer. Cancers 2020, 12, 1026.
77. Cao, M.; Cabrera, R.; Xu, Y.; Liu, C.; Nelson, D. Different radiosensitivity of CD4(+)CD25(+) regulatory T cells and effector T cells to low dose gamma irradiation in vitro. Int. J. Radiat. Biol. 2011, 87, 71–80.
78. Deloch, L.; Derer, A.; Hartmann, J.; Frey, B.; Fietkau, R.; Gaipl, U.S. Modern Radiotherapy Concepts and the Impact of Radiation on Immune Activation. Front. Oncol. 2016, 6, 141.
79. Tsai, M.H.; Cook, J.A.; Chandramouli, G.V.; DeGraff, W.; Yan, H.; Zhao, S.; Coleman, C.N.; Mitchell, J.B.; Chuang, E.Y. Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation. Cancer Res. 2007, 67, 3845–3852.
80. Benci, J.L.; Xu, B.; Qiu, Y.; Wu, T.J.; Dada, H.; Twyman-Saint Victor, C.; Cucolo, L.; Lee, D.S.M.; Pauken, K.E.; Huang, A.C.; et al. Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell 2016, 167, 1540–1554.e1512.
81. Schaue, D.; Ratikan, J.A.; Iwamoto, K.S.; McBride, W.H. Maximizing tumor immunity with fractionated radiation. Int. J. Radiat. Oncol. Biol. Phys. 2012, 83, 1306–1310.
82. De Ruysscher, D.; Waer, M.; Vandeputte, M.; Aerts, R.; Vantongelen, K.; van der Schueren, E. Changes of lymphocyte subsets after local irradiation for early stage breast cancer and seminoma testis: Long-term increase of activated (HLA-DR+) T cells and decrease of “naïve” (CD4-CD45R) T lymphocytes. Eur. J. Cancer 1992, 28, 1729–1734.
83. Vanpouille-Box, C.; Alard, A.; Aryankalayil, M.J.; Sarfraz, Y.; Diamond, J.M.; Schneider, R.J.; Inghirami, G.; Coleman, C.N.; Formenti, S.C.; Demaria, S. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 2017, 8, 15618.
84. Pilones, K.A.; Charpentier, M.; Garcia-Martinez, E.; Daviaud, C.; Kraynak, J.; Aryankalayil, J.; Formenti, S.C.; Demaria, S. Radiotherapy Cooperates with IL15 to Induce Antitumor Immune Responses. Cancer Immunol. Res. 2020, 8, 1054–1063.
85. Harding, S.M.; Benci, J.L.; Irianto, J.; Discher, D.E.; Minn, A.J.; Greenberg, R.A. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 2017, 548, 466–470.
86. Chon, H.; Yoon, K.; Lee, D.; Kwon, D.H.; Cho, Y.H. Single-fraction versus hypofractionated stereotactic radiosurgery for medium-sized brain metastases of 2.5 to 3 cm. J. Neuro-Oncol. 2019, 145, 49–56.
87. Brooks, E.D.; Sun, B.; Zhao, L.; Komaki, R.; Liao, Z.; Jeter, M.; Welsh, J.W.; O’Reilly, M.S.; Gomez, D.R.; Hahn, S.M.; et al. Stereotactic Ablative Radiation Therapy is Highly Safe and Effective for Elderly Patients With Early-stage Non-Small Cell Lung Cancer. Int. J. Radiat. Oncol. Biol. Phys. 2017, 98, 900–907.
88. Levy, A.; Rivera, S. 1-week hypofractionated adjuvant whole-breast radiotherapy: Towards a new standard? Lancet 2020, 395, 1588–1589.
89. Khalife, M.; Shahid, K.; Dabney, R.S.; Phan, A.T. Stereotactic body radiation therapy and immunotherapy. Clin. Adv. Hematol. Oncol. 2019, 17, 518–523.
90. Bernstein, M.B.; Krishnan, S.; Hodge, J.W.; Chang, J.Y. Immunotherapy and stereotactic ablative radiotherapy (ISABR): A curative approach? Nat. Rev. Clin. Oncol. 2016, 13, 516–524.
91. Trovo, M.; Giaj-Levra, N.; Furlan, C.; Bortolin, M.T.; Muraro, E.; Polesel, J.; Minatel, E.; Tedeschi, R.; Filippi, A.R.; Alongi, F.; et al. Stereotactic body radiation therapy and intensity modulated radiation therapy induce different plasmatic cytokine changes in non-small cell lung cancer patients: A pilot study. Clin. Transl. Oncol. 2016, 18, 1003–1010.
92. Chvetsov, A.V.; Rajendran, J.G.; Zeng, J.; Patel, S.A.; Bowen, S.R.; Kim, E.Y. Theoretical effectiveness of cell survival in fractionated radiotherapy with hypoxia-targeted dose escalation. Med. Phys. 2017, 44, 1975–1982.
93. Ko, E.C.; Raben, D.; Formenti, S.C. The Integration of Radiotherapy with Immunotherapy for the Treatment of Non-Small Cell Lung Cancer. Clin. Cancer Res. 2018, 24, 5792–5806.
94. Senthi, S.; Lagerwaard, F.J.; Haasbeek, C.J.; Slotman, B.J.; Senan, S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: A retrospective analysis. Lancet. Oncol. 2012, 13, 802–809.
95. Dewan, M.Z.; Galloway, A.E.; Kawashima, N.; Dewyngaert, J.K.; Babb, J.S.; Formenti, S.C.; Demaria, S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 2009, 15, 5379–5388.
96. Zegers, C.M.L.; Rekers, N.H.; Quaden, D.H.F.; Lieuwes, N.G.; Yaromina, A.; Germeraad, W.T.V.; Wieten, L.; Biessen, E.A.L.; Boon, L.; Neri, D.; et al. Radiotherapy Combined with the Immunocytokine L19-IL2 Provides Long-lasting Antitumor Effects. Clin. Cancer Res. 2015, 21, 1151–1160.
97. Rekers, N.H.; Zegers, C.M.L.; Germeraad, W.T.V.; Dubois, L.; Lambin, P. Long-lasting antitumor effects provided by radiotherapy combined with the immunocytokine L19-IL2. Oncoimmunology 2015, 4, e1021541.
98. Alfonso, J.C.L.; Papaxenopoulou, L.A.; Mascheroni, P.; Meyer-Hermann, M.; Hatzikirou, H. On the Immunological Consequences of Conventionally Fractionated Radiotherapy. Iscience 2020, 23, 100897.
99. Hettich, M.; Lahoti, J.; Prasad, S.; Niedermann, G. Checkpoint Antibodies but not T Cell–Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation. Cancer Res. 2016, 76, 4673–4683.
100. Young, K.H.; Baird, J.R.; Savage, T.; Cottam, B.; Friedman, D.; Bambina, S.; Messenheimer, D.J.; Fox, B.; Newell, P.; Bahjat, K.S.; et al. Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy. PLoS ONE 2016, 11, e0157164.
101. Dovedi, S.J.; Adlard, A.L.; Lipowska-Bhalla, G.; McKenna, C.; Jones, S.; Cheadle, E.J.; Stratford, I.J.; Poon, E.; Morrow, M.; Stewart, R.; et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014, 74, 5458–5468.
102. Lieverse, R.I.Y.; Van Limbergen, E.J.; Oberije, C.J.G.; Troost, E.G.C.; Hadrup, S.R.; Dingemans, A.C.; Hendriks, L.E.L.; Eckert, F.; Hiley, C.; Dooms, C.; et al. Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: A multicentre, randomised controlled open-label phase II trial. BMC Cancer 2020, 20, 557.
103. Perez, C.R.; De Palma, M. Engineering dendritic cell vaccines to improve cancer immunotherapy. Nat. Commun. 2019, 10, 5408.
104. Boudreau, J.E.; Bonehill, A.; Thielemans, K.; Wan, Y. Engineering dendritic cells to enhance cancer immunotherapy. Mol. Ther. 2011, 19, 841–853.
105. Vandenberk, L.; Garg, A.D.; Verschuere, T.; Koks, C.; Belmans, J.; Beullens, M.; Agostinis, P.; De Vleeschouwer, S.; Van Gool, S.W. Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma. Oncoimmunology 2016, 5, e1083669.
106. Rodríguez-Otero, P.; Paiva, B.; Engelhardt, M.; Prósper, F.; San Miguel, J.F. Is immunotherapy here to stay in multiple myeloma? Haematologica 2017, 102, 423–432.
107. Jongbloed, S.L.; Kassianos, A.J.; McDonald, K.J.; Clark, G.J.; Ju, X.; Angel, C.E.; Chen, C.J.; Dunbar, P.R.; Wadley, R.B.; Jeet, V.; et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 2010, 207, 1247–1260.
108. Rapp, M.; Grauer, O.M.; Kamp, M.; Sevens, N.; Zotz, N.; Sabel, M.; Sorg, R.V. A randomized controlled phase II trial of vaccination with lysate-loaded, mature dendritic cells integrated into standard radiochemotherapy of newly diagnosed glioblastoma (GlioVax): Study protocol for a randomized controlled trial. Trials 2018, 19, 293.
109. Rodríguez-Ruiz, M.; Perez-Gracia, J.; Rodríguez, I.; Alfaro, C.; Oñate, C.; Pérez, G.; Gil-Bazo, I.; Benito, A.; Inogés, S.; De Cerio, A.L.-D.; et al. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients. Ann. Oncol. 2018, 29, 1312–1319.
110. Finkelstein, S.E.; Iclozan, C.; Bui, M.M.; Cotter, M.J.; Ramakrishnan, R.; Ahmed, J.; Noyes, D.R.; Cheong, D.; Gonzalez, R.J.; Heysek, R.V.; et al. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. Int. J. Radiat. Oncol. Biol. Phys. 2012, 82, 924–932.
111. Kang, J.; Demaria, S.; Formenti, S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J. Immunother. Cancer 2016, 4, 51.
112. Rosenberg, S.A.; Restifo, N.P.; Yang, J.C.; Morgan, R.A.; Dudley, M.E. Adoptive cell transfer: A clinical path to effective cancer immunotherapy. Nat. Rev. Cancer 2008, 8, 299–308.
113. De Groot, R.; Van Loenen, M.M.; Guislain, A.; Nicolet, B.P.; Freen-Van Heeren, J.J.; Verhagen, O.; Van Den Heuvel, M.M.; De Jong, J.; Burger, P.; Van Der Schoot, C.E.; et al. Polyfunctional tumor-reactive T cells are effectively expanded from non-small cell lung cancers, and correlate with an immune-engaged T cell profile. Oncoimmunology 2019, 8, e1648170.
114. Hinrichs, C.S.; Borman, Z.A.; Cassard, L.; Gattinoni, L.; Spolski, R.; Yu, Z.; Sanchez-Perez, L.; Muranski, P.; Kern, S.J.; Logun, C.; et al. Adoptively transferred effector cells derived from naïve rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc. Natl. Acad. Sci. USA 2009, 106, 17469–17474.
115. Lai, J.Z.; Zhu, Y.Y.; Ruan, M.; Chen, L.; Zhang, Q.Y. Local Irradiation Sensitized Tumors to Adoptive T Cell Therapy via Enhancing the Cross-Priming, Homing, and Cytotoxicity of Antigen-Specific CD8 T Cells. Front. Immunol. 2019, 10, 2857.
116. Ménager, J.; Gorin, J.B.; Maurel, C.; Drujont, L.; Gouard, S.; Louvet, C.; Chérel, M.; Faivre-Chauvet, A.; Morgenstern, A.; Bruchertseifer, F.; et al. Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction. PLoS ONE 2015, 10, e0130249.
117. Wei, S.; Egenti, M.U.; Teitz-Tennenbaum, S.; Zou, W.; Chang, A.E. Effects of tumor irradiation on host T-regulatory cells and systemic immunity in the context of adoptive T-cell therapy in mice. J. Immunother. 2013, 36, 124–132.
118. Jin, L.; Tao, H.; Karachi, A.; Long, Y.; Hou, A.Y.; Na, M.; Dyson, K.A.; Grippin, A.J.; Deleyrolle, L.P.; Zhang, W.; et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat. Commun. 2019, 10, 4016.
119. Kim, K.W.; Jeong, J.U.; Lee, K.H.; Uong, T.N.T.; Rhee, J.H.; Ahn, S.J.; Kim, S.K.; Cho, D.; Quang Nguyen, H.P.; Pham, C.T.; et al. Combined NK Cell Therapy and Radiation Therapy Exhibit Long-Term Therapeutic and Antimetastatic Effects in a Human Triple Negative Breast Cancer Model. Int. J. Radiat. Oncol. Biol. Phys. 2020, 108, 115–125.
120. DeSelm, C.; Palomba, M.L.; Yahalom, J.; Hamieh, M.; Eyquem, J.; Rajasekhar, V.K.; Sadelain, M. Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape. Mol. Ther. 2018, 26, 2542–2552.
121. Sim, A.J.; Jain, M.D.; Figura, N.B.; Chavez, J.C.; Shah, B.D.; Khimani, F.; Lazaryan, A.; Krivenko, G.; Davila, M.L.; Liu, H.D.; et al. Radiation Therapy as a Bridging Strategy for CAR T Cell Therapy With Axicabtagene Ciloleucel in Diffuse Large B-Cell Lymphoma. Int. J. Radiat. Oncol. Biol. Phys. 2019, 105, 1012–1021.
122. Vascotto, F.; Petschenka, J.; Walzer, K.C.; Vormehr, M.; Brkic, M.; Strobl, S.; Rösemann, R.; Diken, M.; Kreiter, S.; Türeci, Ö.; et al. Intravenous delivery of the toll-like receptor 7 agonist SC1 confers tumor control by inducing a CD8+ T cell response. Oncoimmunology 2019, 8, 1601480.
123. Larkin, B.; Ilyukha, V.; Sorokin, M.; Buzdin, A.; Vannier, E.; Poltorak, A. Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death. J. Immunol. 2017, 199, 397–402.
124. Knee, D.A.; Hewes, B.; Brogdon, J.L. Rationale for anti-GITR cancer immunotherapy. Eur. J. Cancer 2016, 67, 1–10.
125. Von Karstedt, S.; Montinaro, A.; Walczak, H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer 2017, 17, 352–366.
126. Cohen, A.D.; Diab, A.; Perales, M.A.; Wolchok, J.D.; Rizzuto, G.; Merghoub, T.; Huggins, D.; Liu, C.; Turk, M.J.; Restifo, N.P.; et al. Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res. 2006, 66, 4904–4912.
127. Fu, J.; Kanne, D.B.; Leong, M.; Glickman, L.H.; McWhirter, S.M.; Lemmens, E.; Mechette, K.; Leong, J.J.; Lauer, P.; Liu, W.; et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl. Med. 2015, 7, 283ra252.
128. Dewan, M.Z.; Vanpouille-Box, C.; Kawashima, N.; DiNapoli, S.; Babb, J.S.; Formenti, S.C.; Adams, S.; Demaria, S. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin. Cancer Res. 2012, 18, 6668–6678.
129. Dovedi, S.J.; Adlard, A.L.; Ota, Y.; Murata, M.; Sugaru, E.; Koga-Yamakawa, E.; Eguchi, K.; Hirose, Y.; Yamamoto, S.; Umehara, H.; et al. Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy. Oncotarget 2016, 7, 17035–17046.
130. Yokouchi, H.; Yamazaki, K.; Chamoto, K.; Kikuchi, E.; Shinagawa, N.; Oizumi, S.; Hommura, F.; Nishimura, T.; Nishimura, M. Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer. Cancer Sci. 2008, 99, 361–367.
131. Mason, K.A.; Neal, R.; Hunter, N.; Ariga, H.; Ang, K.; Milas, L. CpG oligodeoxynucleotides are potent enhancers of radio- and chemoresponses of murine tumors. Radiother. Oncol. 2006, 80, 192–198.
132. Monjazeb, A.M.; Kent, M.S.; Grossenbacher, S.K.; Mall, C.; Zamora, A.E.; Mirsoian, A.; Chen, M.; Kol, A.; Shiao, S.L.; Reddy, A.; et al. Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies. Clin. Cancer Res. 2016, 22, 4328–4340.
133. Meng, Y.; Carpentier, A.F.; Chen, L.; Boisserie, G.; Simon, J.M.; Mazeron, J.J.; Delattre, J.Y. Successful combination of local CpG-ODN and radiotherapy in malignant glioma. Int. J. Cancer 2005, 116, 992–997.
134. Kim, Y.H.; Gratzinger, D.; Harrison, C.; Brody, J.D.; Czerwinski, D.K.; Ai, W.Z.; Morales, A.; Abdulla, F.; Xing, L.; Navi, D.; et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: A phase 1/2 study. Blood 2012, 119, 355–363.
135. Brody, J.D.; Ai, W.Z.; Czerwinski, D.K.; Torchia, J.A.; Levy, M.; Advani, R.H.; Kim, Y.H.; Hoppe, R.T.; Knox, S.J.; Shin, L.K.; et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: A phase I/II study. J. Clin. Oncol. 2010, 28, 4324–4332.
136. Payne, R.; Glenn, L.; Hoen, H.; Richards, B.; Smith, J.W., 2nd; Lufkin, R.; Crocenzi, T.S.; Urba, W.J.; Curti, B.D. Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program. J. Immunother. Cancer 2014, 2, 13.
137. Conlon, K.C.; Miljkovic, M.D.; Waldmann, T.A. Cytokines in the Treatment of Cancer. J. Interferon Cytokine Res. 2018, 39, 6–21.
138. Alwan, L.M.; Grossmann, K.; Sageser, D.; Van Atta, J.; Agarwal, N.; Gilreath, J.A. Comparison of acute toxicity and mortality after two different dosing regimens of high-dose interleukin-2 for patients with metastatic melanoma. Target. Oncol. 2014, 9, 63–71.
139. Kontermann, R.E. Antibody-cytokine fusion proteins. Arch. Biochem. Biophys. 2012, 526, 194–205.
140. List, T.; Neri, D. Immunocytokines: A review of molecules in clinical development for cancer therapy. Clin. Pharmacol. 2013, 5, 29–45.
141. Létourneau, S.; van Leeuwen, E.M.; Krieg, C.; Martin, C.; Pantaleo, G.; Sprent, J.; Surh, C.D.; Boyman, O. IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25. Proc. Natl. Acad. Sci. USA 2010, 107, 2171–2176.
142. Mortara, L.; Balza, E.; Bruno, A.; Poggi, A.; Orecchia, P.; Carnemolla, B. Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy. Front. Immunol. 2018, 9, 2905.
143. Lieverse, R.I.Y.; Marcus, D.; van der Wiel, A.M.A.; Van Limbergen, E.J.; Theys, J.; Yaromina, A.; Lambin, P.; Dubois, L.J. Human fibronectin extra domain B as a biomarker for targeted therapy in cancer. Mol. Oncol. 2020, 14, 1555–1568.
144. Palata, O.; Hradilova Podzimkova, N.; Nedvedova, E.; Umprecht, A.; Sadilkova, L.; Palova Jelinkova, L.; Spisek, R.; Adkins, I. Radiotherapy in Combination With Cytokine Treatment. Front. Oncol. 2019, 9, 367.
145. Van den Heuvel, M.M.; Verheij, M.; Boshuizen, R.; Belderbos, J.; Dingemans, A.M.; De Ruysscher, D.; Laurent, J.; Tighe, R.; Haanen, J.; Quaratino, S. NHS-IL2 combined with radiotherapy: Preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy. J. Transl. Med. 2015, 13, 32.
146. Morris, Z.S.; Guy, E.I.; Francis, D.M.; Gressett, M.M.; Werner, L.R.; Carmichael, L.L.; Yang, R.K.; Armstrong, E.A.; Huang, S.; Navid, F.; et al. In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. Cancer Res. 2016, 76, 3929–3941.
147. Voeller, J.; Erbe, A.K.; Slowinski, J.; Rasmussen, K.; Carlson, P.M.; Hoefges, A.; VandenHeuvel, S.; Stuckwisch, A.; Wang, X.; Gillies, S.D.; et al. Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. J. Immunother. Cancer 2019, 7, 344.
148. Kujawski, M.; Sherman, M.; Hui, S.; Zuro, D.; Lee, W.H.; Yazaki, P.; Sherman, A.; Szpikowska, B.; Chea, J.; Lasiewski, D.; et al. Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation. Oncoimmunology 2020, 9, 1724052.
149. Rekers, N.H.; Olivo Pimentel, V.; Yaromina, A.; Lieuwes, N.G.; Biemans, R.; Zegers, C.M.L.; Germeraad, W.T.V.; Van Limbergen, E.J.; Neri, D.; Dubois, L.J.; et al. The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses. Oncoimmunology 2018, 7, e1414119.
150. Van Limbergen, E.J.; Hoeben, A.; Lieverse, R.; Houben, R.; Overhof, C.; Postma, A.; Zindler, J.; Verhelst, F.; Dubois, L.J.; De Ruysscher, D.; et al. Toxicity of L19-Interleukin 2 combined with Stereotactic Body Radiotherapy: A phase 1 study. Int. J. Radiat. Oncol. Biol. Phys. 2021, 109, 1421–1430.
151. Zorn, E.; Nelson, E.A.; Mohseni, M.; Porcheray, F.; Kim, H.; Litsa, D.; Bellucci, R.; Raderschall, E.; Canning, C.; Soiffer, R.J.; et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006, 108, 1571–1579.
152. Fallon, J.; Tighe, R.; Kradjian, G.; Guzman, W.; Bernhardt, A.; Neuteboom, B.; Lan, Y.; Sabzevari, H.; Schlom, J.; Greiner, J.W. The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget 2014, 5, 1869–1884.
153. Eckert, F.; Jelas, I.; Oehme, M.; Huber, S.M.; Sonntag, K.; Welker, C.; Gillies, S.D.; Strittmatter, W.; Zips, D.; Handgretinger, R.; et al. Tumor-targeted IL-12 combined with local irradiation leads to systemic tumor control via abscopal effects in vivo. Oncoimmunology 2017, 6, e1323161.
154. Sardana, R.; Mishra, S.K.; Williamson, S.R.; Mohanty, A.; Mohanty, S.K. Immune checkpoints and their inhibitors: Reappraisal of a novel diagnostic and therapeutic dimension in the urologic malignancies. Semin. Oncol. 2020, 47, 367–379.
155. Vanneste, B.G.L.; Van Limbergen, E.J.; Dubois, L.; Samarska, I.V.; Wieten, L.; Aarts, M.J.B.; Marcelissen, T.; De Ruysscher, D. Immunotherapy as sensitizer for local radiotherapy. Oncoimmunology 2020, 9, 1832760.
156. Ullah, M.; Aoudjeghout, W.; Pimpie, C.; Pocard, M.; Mirshahi, M. Mitosis in Cancer Cell Increases Immune Resistance via High Expression of HLA-G and PD-L1. Cancers 2020, 12, 2661.
157. Herter-Sprie, G.S.; Koyama, S.; Korideck, H.; Hai, J.; Deng, J.; Li, Y.Y.; Buczkowski, K.A.; Grant, A.K.; Ullas, S.; Rhee, K.; et al. Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight 2016, 1, e87415.
158. Oweida, A.; Lennon, S.; Calame, D.; Korpela, S.; Bhatia, S.; Sharma, J.; Graham, C.; Binder, D.; Serkova, N.; Raben, D.; et al. Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. Oncoimmunology 2017, 6, e1356153.
159. Zeng, J.; See, A.P.; Phallen, J.; Jackson, C.M.; Belcaid, Z.; Ruzevick, J.; Durham, N.; Meyer, C.; Harris, T.J.; Albesiano, E.; et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int. J. Radiat. Oncol. Biol. Phys. 2013, 86, 343–349.
160. Sharabi, A.B.; Nirschl, C.J.; Kochel, C.M.; Nirschl, T.R.; Francica, B.J.; Velarde, E.; Deweese, T.L.; Drake, C.G. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen. Cancer Immunol. Res. 2015, 3, 345–355.
161. Rudqvist, N.P.; Pilones, K.A.; Lhuillier, C.; Wennerberg, E.; Sidhom, J.W.; Emerson, R.O.; Robins, H.S.; Schneck, J.; Formenti, S.C.; Demaria, S. Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells. Cancer Immunol. Res. 2018, 6, 139–150.
162. Demaria, S.; Kawashima, N.; Yang, A.M.; Devitt, M.L.; Babb, J.S.; Allison, J.P.; Formenti, S.C. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 2005, 11, 728–734.
163. Son, C.H.; Bae, J.H.; Shin, D.Y.; Lee, H.R.; Choi, Y.J.; Jo, W.S.; Ho Jung, M.; Kang, C.D.; Yang, K.; Park, Y.S. CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model. J. Immunother. 2014, 37, 1–7.
164. Formenti, S.C.; Rudqvist, N.P.; Golden, E.; Cooper, B.; Wennerberg, E.; Lhuillier, C.; Vanpouille-Box, C.; Friedman, K.; Ferrari de Andrade, L.; Wucherpfennig, K.W.; et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 2018, 24, 1845–1851.
165. Golden, E.B.; Demaria, S.; Schiff, P.B.; Chachoua, A.; Formenti, S.C. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol. Res. 2013, 1, 365–372.
166. Postow, M.A.; Callahan, M.K.; Barker, C.A.; Yamada, Y.; Yuan, J.; Kitano, S.; Mu, Z.; Rasalan, T.; Adamow, M.; Ritter, E.; et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 2012, 366, 925–931.
167. Tang, C.; Welsh, J.W.; De Groot, P.; Massarelli, E.; Chang, J.Y.; Hess, K.R.; Basu, S.; Curran, M.A.; Cabanillas, M.E.; Subbiah, V.; et al. Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells. Clinical Cancer Res. 2017, 23, 1388–1396.
168. Roger, A.; Finet, A.; Boru, B.; Beauchet, A.; Mazeron, J.J.; Otzmeguine, Y.; Blom, A.; Longvert, C.; de Maleissye, M.F.; Fort, M.; et al. Efficacy of combined hypo-fractionated radiotherapy and anti-PD-1 monotherapy in difficult-to-treat advanced melanoma patients. Oncoimmunology 2018, 7, e1442166.
169. Luke, J.J.; Lemons, J.M.; Karrison, T.G.; Pitroda, S.P.; Melotek, J.M.; Zha, Y.; Al-Hallaq, H.A.; Arina, A.; Khodarev, N.N.; Janisch, L.; et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. J. Clin. Oncol. 2018, 36, 1611–1618.
170. Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Yokoi, T.; Chiappori, A.; Lee, K.H.; de Wit, M.; et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2017, 377, 1919–1929.
171. Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Kurata, T.; Chiappori, A.; Lee, K.H.; de Wit, M.; et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N. Engl. J. Med. 2018, 379, 2342–2350.
172. Hui, R.; Özgüroğlu, M.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Yokoi, T.; Chiappori, A.; Lee, K.H.; De Wit, M.; et al. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): A randomised, controlled, phase 3 study. Lancet Oncol. 2019, 20, 1670–1680.
173. Watanabe, T.; Gaedicke, S.; Guffart, E.; Firat, E.; Niedermann, G. Adding Indoximod to Hypofractionated Radiotherapy with Anti-PD-1 Checkpoint Blockade Enhances Early NK and CD8(+) T-Cell-Dependent Tumor Activity. Clin. Cancer Res. 2020, 26, 945–956.
174. Cohen, E.E.; Ferris, R.L.; Psyrri, A.; Haddad, R.; Tahara, M.; Bourhis, J.; Harrington, K.J.; Chang, P.M.H.; Lin, J.C.; Razaq, M.; et al. 910O Primary results of the phase III JAVELIN head & neck 100 trial: Avelumab plus chemoradiotherapy (CRT) followed by avelumab maintenance vs CRT in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Ann. Oncol. 2020, 31, S658.
175. Bourhis, J.; Sire, C.; Tao, Y.; Martin, L.; Alfonsi, M.; Prevost, J.B.; Rives, M.; Lafond, C.; Tourani, J.M.; Biau, J.; et al. LBA38 Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the GORTEC 2015-01 “PembroRad” randomized trial. Ann. Oncol. 2020, 31, S1168.
176. Vinay, D.S.; Ryan, E.P.; Pawelec, G.; Talib, W.H.; Stagg, J.; Elkord, E.; Lichtor, T.; Decker, W.K.; Whelan, R.L.; Kumara, H.; et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 2015, 35, S185–S198.
177. Qin, S.; Xu, L.; Yi, M.; Yu, S.; Wu, K.; Luo, S. Novel immune checkpoint targets: Moving beyond PD-1 and CTLA-4. Mol. Cancer 2019, 18, 155.
178. Poggio, M.; Hu, T.; Pai, C.C.; Chu, B.; Belair, C.D.; Chang, A.; Montabana, E.; Lang, U.E.; Fu, Q.; Fong, L.; et al. Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory. Cell 2019, 177, 414–427.e413.
179. Moynihan, K.D.; Opel, C.F.; Szeto, G.L.; Tzeng, A.; Zhu, E.F.; Engreitz, J.M.; Williams, R.T.; Rakhra, K.; Zhang, M.H.; Rothschilds, A.M.; et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 2016, 22, 1402–1410.
180. Olivo Pimentel, V.; Marcus, D.; van der Wiel, A.M.; Lieuwes, N.G.; Biemans, R.; Lieverse, R.I.; Neri, D.; Theys, J.; Yaromina, A.; Dubois, L.J.; et al. Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19-IL2 cures poorly immunogenic tumors when combined with radiotherapy. J. Immunother. Cancer 2021, 9.
181. Bai, R.; Lv, Z.; Xu, D.; Cui, J. Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomark. Res. 2020, 8, 34.
182. Sun, R.; Limkin, E.J.; Vakalopoulou, M.; Dercle, L.; Champiat, S.; Han, S.R.; Verlingue, L.; Brandao, D.; Lancia, A.; Ammari, S.; et al. A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: An imaging biomarker, retrospective multicohort study. Lancet Oncol. 2018, 19, 1180–1191.
183. Jang, B.S.; Kim, I.A. A radiosensitivity gene signature and PD-L1 status predict clinical outcome of patients with invasive breast carcinoma in The Cancer Genome Atlas (TCGA) dataset. Radiother. Oncol. 2017, 124, 403–410.
184. Debus, C.; Afshar-Oromieh, A.; Floca, R.; Ingrisch, M.; Knoll, M.; Debus, J.; Haberkorn, U.; Abdollahi, A. Feasibility and robustness of dynamic (18)F-FET PET based tracer kinetic models applied to patients with recurrent high-grade glioma prior to carbon ion irradiation. Sci. Rep. 2018, 8, 14760.
185. Debus, C.; Waltenberger, M.; Floca, R.; Afshar-Oromieh, A.; Bougatf, N.; Adeberg, S.; Heiland, S.; Bendszus, M.; Wick, W.; Rieken, S.; et al. Impact of (18)F-FET PET on Target Volume Definition and Tumor Progression of Recurrent High Grade Glioma Treated with Carbon-Ion Radiotherapy. Sci. Rep. 2018, 8, 7201.
186. Zhou, C.; Jones, B.; Moustafa, M.; Schwager, C.; Bauer, J.; Yang, B.; Cao, L.; Jia, M.; Mairani, A.; Chen, M.; et al. Quantitative assessment of radiation dose and fractionation effects on normal tissue by utilizing a novel lung fibrosis index model. Radiat. Oncol. 2017, 12, 172.
187. Zhou, C.; Jones, B.; Moustafa, M.; Yang, B.; Brons, S.; Cao, L.; Dai, Y.; Schwager, C.; Chen, M.; Jaekel, O.; et al. Determining RBE for development of lung fibrosis induced by fractionated irradiation with carbon ions utilizing fibrosis index and high-LET BED model. Clin. Transl. Radiat. Oncol. 2019, 14, 25–32.
188. Zhou, C.; Moustafa, M.R.; Cao, L.; Kriegsmann, M.; Winter, M.; Schwager, C.; Jones, B.; Wang, S.; Bauerle, T.; Zhou, P.K.; et al. Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation. Int. J. Cancer 2019, 144, 3160–3173.
189. Nowrouzi, A.; Sertorio, M.G.; Akbarpour, M.; Knoll, M.; Krunic, D.; Kuhar, M.; Schwager, C.; Brons, S.; Debus, J.; Wells, S.I.; et al. Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids. Cancers 2020, 12, 469.
190. Mohamad, O.; Sishc, B.J.; Saha, J.; Pompos, A.; Rahimi, A.; Story, M.D.; Davis, A.J.; Kim, D.W.N. Carbon Ion Radiotherapy: A Review of Clinical Experiences and Preclinical Research, with an Emphasis on DNA Damage/Repair. Cancers 2017, 9, 66.
191. Mein, S.; Klein, C.; Kopp, B.; Magro, G.; Harrabi, S.; Karger, C.P.; Haberer, T.; Debus, J.; Abdollahi, A.; Dokic, I.; et al. Assessment of RBE-Weighted Dose Models for Carbon Ion Therapy Toward Modernization of Clinical Practice at HIT: In Vitro, in Vivo, and in Patients. Int. J. Radiat. Oncol. Biol. Phys. 2020, 108, 779–791.
192. Bronk, L.; Guan, F.; Patel, D.; Ma, D.; Kroger, B.; Wang, X.; Tran, K.; Yiu, J.; Stephan, C.; Debus, J.; et al. Mapping the Relative Biological Effectiveness of Proton, Helium and Carbon Ions with High-Throughput Techniques. Cancers 2020, 12, 3658.
193. Winter, M.; Dokic, I.; Schlegel, J.; Warnken, U.; Debus, J.; Abdollahi, A.; Schnolzer, M. Deciphering the Acute Cellular Phosphoproteome Response to Irradiation with X-rays, Protons and Carbon Ions. Mol. Cell Proteom. 2017, 16, 855–872.
194. Dai, Y.; Wei, Q.; Schwager, C.; Hanne, J.; Zhou, C.; Herfarth, K.; Rieken, S.; Lipson, K.E.; Debus, J.; Abdollahi, A. Oncogene addiction and radiation oncology: Effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC. Radiat. Oncol. 2018, 13, 1.
195. Dai, Y.; Wei, Q.; Schwager, C.; Moustafa, M.; Zhou, C.; Lipson, K.E.; Weichert, W.; Debus, J.; Abdollahi, A. Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer. Radiother. Oncol. 2015, 114, 173–181.
196. Ando, K.; Koike, S.; Uzawa, A.; Takai, N.; Fukawa, T.; Furusawa, Y.; Aoki, M.; Miyato, Y. Biological gain of carbon-ion radiotherapy for the early response of tumor growth delay and against early response of skin reaction in mice. J. Radiat. Res. 2005, 46, 51–57.
197. Shirai, K.; Kubota, Y.; Ohno, T.; Saitoh, J.I.; Abe, T.; Mizukami, T.; Mori, Y.; Kawamura, H.; Akahane, K.; Nakano, T. Carbon-ion Radiotherapy for Isolated Lymph Node Metastasis After Surgery or Radiotherapy for Lung Cancer. Front. Oncol. 2019, 9, 731.
198. Sato, K.; Shimokawa, T.; Imai, T. Difference in Acquired Radioresistance Induction Between Repeated Photon and Particle Irradiation. Front. Oncol. 2019, 9, 1213.
199. Tommasino, F.; Durante, M. Proton radiobiology. Cancers 2015, 7, 353–381.
200. Tinganelli, W.; Durante, M. Carbon Ion Radiobiology. Cancers 2020, 12, 3022.
201. Durante, M.; Loeffler, J.S. Charged particles in radiation oncology. Nat. Rev. Clin. Oncol. 2010, 7, 37–43.
202. Terasawa, T.; Dvorak, T.; Ip, S.; Raman, G.; Lau, J.; Trikalinos, T.A. Systematic review: Charged-particle radiation therapy for cancer. Ann. Intern. Med. 2009, 151, 556–565.
203. Debus, J.; Abdollahi, A. For the next trick: New discoveries in radiobiology applied to glioblastoma. Am. Soc. Clin. Oncol. Educ. Book 2014, e95–e99.
204. Onishi, M.; Okonogi, N.; Oike, T.; Yoshimoto, Y.; Sato, H.; Suzuki, Y.; Kamada, T.; Nakano, T. High linear energy transfer carbon-ion irradiation increases the release of the immune mediator high mobility group box 1 from human cancer cells. J. Radiat. Res. 2018, 59, 541–546.
205. Murshed, H. Fundamentals of Radiation Oncology, 3rd ed.; Elsevier Science: San Diego, CA, USA, 2019; p. 746.
206. Yoshimoto, Y.; Kono, K.; Suzuki, Y. Anti-tumor immune responses induced by radiotherapy: A review. Fukushima J. Med. Sci. 2015, 61, 13–22.
207. Ando, K.; Fujita, H.; Hosoi, A.; Ma, L.; Wakatsuki, M.; Seino, K.-i.; Kakimi, K.; Imai, T.; Shimokawa, T.; Nakano, T. Intravenous dendritic cell administration enhances suppression of lung metastasis induced by carbon-ion irradiation. J. Radiat. Res. 2017, 58, 446–455.
208. Gameiro, S.R.; Malamas, A.S.; Bernstein, M.B.; Tsang, K.Y.; Vassantachart, A.; Sahoo, N.; Tailor, R.; Pidikiti, R.; Guha, C.P.; Hahn, S.M.; et al. Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell-Mediated Killing. Int. J. Radiat. Oncol. Biol. Phys. 2016, 95, 120–130.
209. Huang, Y.; Dong, Y.; Zhao, J.; Zhang, L.; Kong, L.; Lu, J.J. Comparison of the effects of photon, proton and carbon-ion radiation on the ecto-calreticulin exposure in various tumor cell lines. Ann. Transl. Med. 2019, 7, 542.
210. Garg, A.D.; De Ruysscher, D.; Agostinis, P. Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis. Oncoimmunology 2016, 5, e1069938.
211. Bao, C.; Sun, Y.; Dwarakanath, B.; Dong, Y.; Huang, Y.; Wu, X.; Guha, C.; Kong, L.; Lu, J.J. Carbon ion triggered immunogenic necroptosis of nasopharyngeal carcinoma cells involving necroptotic inhibitor BCL-x. J. Cancer 2021, 12, 1520–1530.
212. Alan Mitteer, R.; Wang, Y.; Shah, J.; Gordon, S.; Fager, M.; Butter, P.P.; Jun Kim, H.; Guardiola-Salmeron, C.; Carabe-Fernandez, A.; Fan, Y. Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species. Sci. Rep. 2015, 5, 13961.
213. Georgakilas, A.G.; O’Neill, P.; Stewart, R.D. Induction and repair of clustered DNA lesions: What do we know so far? Radiat. Res. 2013, 180, 100–109.
214. Oonishi, K.; Cui, X.; Hirakawa, H.; Fujimori, A.; Kamijo, T.; Yamada, S.; Yokosuka, O.; Kamada, T. Different effects of carbon ion beams and X-rays on clonogenic survival and DNA repair in human pancreatic cancer stem-like cells. Radiother. Oncol. 2012, 105, 258–265.
215. Morishita, M.; Muramatsu, T.; Suto, Y.; Hirai, M.; Konishi, T.; Hayashi, S.; Shigemizu, D.; Tsunoda, T.; Moriyama, K.; Inazawa, J. Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system. Oncotarget 2016, 7, 10182–10192.
216. Rode, A.; Maass, K.K.; Willmund, K.V.; Lichter, P.; Ernst, A. Chromothripsis in cancer cells: An update. Int. J. Cancer 2016, 138, 2322–2333.
217. Helm, A.; Lee, R.; Durante, M.; Ritter, S. The Influence of C-Ions and X-rays on Human Umbilical Vein Endothelial Cells. Front. Oncol. 2016, 6, 5.
218. Litvinchuk, A.V.; Vachelová, J.; Michaelidesová, A.; Wagner, R.; Davídková, M. Dose-dependent micronuclei formation in normal human fibroblasts exposed to proton radiation. Radiat. Environ. Biophys. 2015, 54, 327–334.
219. Autsavapromporn, N.; Plante, I.; Liu, C.; Konishi, T.; Usami, N.; Funayama, T.; Azzam, E.I.; Murakami, T.; Suzuki, M. Genetic changes in progeny of bystander human fibroblasts after microbeam irradiation with X-rays, protons or carbon ions: The relevance to cancer risk. Int. J. Radiat. Biol. 2015, 91, 62–70.
220. Carter, R.J.; Nickson, C.M.; Thompson, J.M.; Kacperek, A.; Hill, M.A.; Parsons, J.L. Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response. Int. J. Radiat. Oncol. Biol. Phys. 2018, 100, 776–784.
221. Tarcic, O.; Pateras, I.S.; Cooks, T.; Shema, E.; Kanterman, J.; Ashkenazi, H.; Boocholez, H.; Hubert, A.; Rotkopf, R.; Baniyash, M.; et al. RNF20 Links Histone H2B Ubiquitylation with Inflammation and Inflammation-Associated Cancer. Cell Rep. 2016, 14, 1462–1476.
222. Melzig, C.; Golestaneh, A.F.; Mier, W.; Schwager, C.; Das, S.; Schlegel, J.; Lasitschka, F.; Kauczor, H.U.; Debus, J.; Haberkorn, U.; et al. Combined external beam radiotherapy with carbon ions and tumor targeting endoradiotherapy. Oncotarget 2018, 9, 29985–30004.
223. Chiblak, S.; Tang, Z.; Campos, B.; Gal, Z.; Unterberg, A.; Debus, J.; Herold-Mende, C.; Abdollahi, A. Radiosensitivity of Patient-Derived Glioma Stem Cell 3-Dimensional Cultures to Photon, Proton, and Carbon Irradiation. Int. J. Radiat. Oncol. Biol. Phys. 2016, 95, 112–119.
224. Lupu-Plesu, M.; Claren, A.; Martial, S.; N’Diaye, P.D.; Lebrigand, K.; Pons, N.; Ambrosetti, D.; Peyrottes, I.; Feuillade, J.; Hérault, J.; et al. Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma. Oncogenesis 2017, 6, e354.
225. Nielsen, S.; Bassler, N.; Grzanka, L.; Swakon, J.; Olko, P.; Horsman, M.R.; Sørensen, B.S. Proton scanning and X-ray beam irradiation induce distinct regulation of inflammatory cytokines in a preclinical mouse model. Int. J. Radiat. Biol. 2020, 96, 1238–1244.
226. Nielsen, S.; Bassler, N.; Grzanka, L.; Laursen, L.; Swakon, J.; Olko, P.; Andreassen, C.N.; Alsner, J.; Singers Sørensen, B. Comparison of Coding Transcriptomes in Fibroblasts Irradiated With Low and High LET Proton Beams and Cobalt-60 Photons. Int. J. Radiat. Oncol. Biol. Phys. 2019, 103, 1203–1211.
227. Nielsen, S.; Bassler, N.; Grzanka, L.; Swakon, J.; Olko, P.; Andreassen, C.N.; Overgaard, J.; Alsner, J.; Sørensen, B.S. Differential gene expression in primary fibroblasts induced by proton and cobalt-60 beam irradiation. Acta Oncol. 2017, 56, 1406–1412.
228. Chouaib, S.; Umansky, V.; Kieda, C. The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment. Contemp. Oncol. 2018, 22, 7–13.
229. Labiano, S.; Palazon, A.; Melero, I. Immune response regulation in the tumor microenvironment by hypoxia. Semin. Oncol. 2015, 42, 378–386.
230. Park, J.E.; Dutta, B.; Tse, S.W.; Gupta, N.; Tan, C.F.; Low, J.K.; Yeoh, K.W.; Kon, O.L.; Tam, J.P.; Sze, S.K. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene 2019, 38, 5158–5173.
231. Noman, M.Z.; Hasmim, M.; Messai, Y.; Terry, S.; Kieda, C.; Janji, B.; Chouaib, S. Hypoxia: A key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia. Am. J. Physiol. Cell Physiol. 2015, 309, C569–C579.
232. Barsoum, I.B.; Smallwood, C.A.; Siemens, D.R.; Graham, C.H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014, 74, 665–674.
233. Noman, M.Z.; Desantis, G.; Janji, B.; Hasmim, M.; Karray, S.; Dessen, P.; Bronte, V.; Chouaib, S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 2014, 211, 781–790.
234. Subtil, F.S.; Wilhelm, J.; Bill, V.; Westholt, N.; Rudolph, S.; Fischer, J.; Scheel, S.; Seay, U.; Fournier, C.; Taucher-Scholz, G.; et al. Carbon ion radiotherapy of human lung cancer attenuates HIF-1 signaling and acts with considerably enhanced therapeutic efficiency. FASEB J. 2014, 28, 1412–1421.
235. Wozny, A.S.; Lauret, A.; Battiston-Montagne, P.; Guy, J.B.; Beuve, M.; Cunha, M.; Saintigny, Y.; Blond, E.; Magne, N.; Lalle, P.; et al. Differential pattern of HIF-1α expression in HNSCC cancer stem cells after carbon ion or photon irradiation: One molecular explanation of the oxygen effect. Br. J. Cancer 2017, 116, 1340–1349.
236. Klein, C.; Dokic, I.; Mairani, A.; Mein, S.; Brons, S.; Haring, P.; Haberer, T.; Jakel, O.; Zimmermann, A.; Zenke, F.; et al. Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation. Radiat. Oncol. 2017, 12, 208.
237. Chiblak, S.; Tang, Z.; Lemke, D.; Knoll, M.; Dokic, I.; Warta, R.; Moustafa, M.; Mier, W.; Brons, S.; Rapp, C.; et al. Carbon irradiation overcomes glioma radioresistance by eradicating stem cells and forming an antiangiogenic and immunopermissive niche. JCI Insight 2019, 4, e123837.
238. Ogata, T.; Teshima, T.; Kagawa, K.; Hishikawa, Y.; Takahashi, Y.; Kawaguchi, A.; Suzumoto, Y.; Nojima, K.; Furusawa, Y.; Matsuura, N. Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res. 2005, 65, 113–120.
239. Mohamad, O.; Tabuchi, T.; Nitta, Y.; Nomoto, A.; Sato, A.; Kasuya, G.; Makishima, H.; Choy, H.; Yamada, S.; Morishima, T.; et al. Risk of subsequent primary cancers after carbon ion radiotherapy, photon radiotherapy, or surgery for localised prostate cancer: A propensity score-weighted, retrospective, cohort study. Lancet Oncol. 2019, 20, 674–685.
240. Matsunaga, A.; Ueda, Y.; Yamada, S.; Harada, Y.; Shimada, H.; Hasegawa, M.; Tsujii, H.; Ochiai, T.; Yonemitsu, Y. Carbon-ion beam treatment induces systemic antitumor immunity against murine squamous cell carcinoma. Cancer 2010, 116, 3740–3748.
241. Tamaki, T.; Iwakawa, M.; Ohno, T.; Imadome, K.; Nakawatari, M.; Sakai, M.; Tsujii, H.; Nakano, T.; Imai, T. Application of Carbon-Ion Beams or Gamma-Rays on Primary Tumors Does Not Change the Expression Profiles of Metastatic Tumors in an In Vivo Murine Model. Int. J. Radiat. Oncol. Biol. Phys. 2009, 74, 210–218.
242. Brenneman, R.J.; Sharifai, N.; Fischer-Valuck, B.; Hassanzadeh, C.; Guzelian, J.; Chrisinger, J.S.A.; Michalski, J.M.; Oppelt, P.; Baumann, B.C. Abscopal Effect Following Proton Beam Radiotherapy in a Patient With Inoperable Metastatic Retroperitoneal Sarcoma. Front. Oncol. 2019, 9, 922.
243. Takahashi, Y.; Yasui, T.; Minami, K.; Tamari, K.; Hayashi, K.; Otani, K.; Seo, Y.; Isohashi, F.; Koizumi, M.; Ogawa, K. Carbon ion irradiation enhances the antitumor efficacy of dual immune checkpoint blockade therapy both for local and distant sites in murine osteosarcoma. Oncotarget 2019, 10, 633–646.
244. Shimokawa, T.; Ma, L.; Ando, K.; Sato, K.; Imai, T. The Future of Combining Carbon-Ion Radiotherapy with Immunotherapy: Evidence and Progress in Mouse Models. Int. J. Part. Ther. 2016, 3, 61–70.
245. Ohkubo, Y.; Iwakawa, M.; Seino, K.; Nakawatari, M.; Wada, H.; Kamijuku, H.; Nakamura, E.; Nakano, T.; Imai, T. Combining carbon ion radiotherapy and local injection of α-galactosylceramide-pulsed dendritic cells inhibits lung metastases in an in vivo murine model. Int. J. Radiat. Oncol. Biol. Phys. 2010, 78, 1524–1531.
246. Helm, A.; Tinganelli, W.; Simoniello, P.; Kurosawa, F.; Fournier, C.; Shimokawa, T.; Durante, M. Reduction of Lung Metastases in a Mouse Osteosarcoma Model Treated With Carbon Ions and Immune Checkpoint Inhibitors. Int. J. Radiat. Oncol. Biol. Phys. 2020, 109, 594–602.
247. Brownstein, J.M.; Wisdom, A.J.; Castle, K.D.; Mowery, Y.M.; Guida, P.; Lee, C.L.; Tommasino, F.; Tessa, C.; Scifoni, E.; Gao, J.; et al. Characterizing the Potency and Impact of Carbon Ion Therapy in a Primary Mouse Model of Soft Tissue Sarcoma. Mol. Cancer Ther. 2018, 17, 858–868.