Radio-Immunotherapy: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Chunlin SHAO.

Radio-Immunotherapy: the combination effect of radiotherapy and immunotherapy on tumors, which may have much better therapeutic efficacy than each of them alone.

  • radiotherapy
  • anti-tumor abscopal effect
  • bystander effect
  • immunomodulation
  • immune checkpoint
  • immunotherapy
  • damage-associated molecular patterns (DAMPs)

1. Introduction 

The impact of radiotherapy (RT) on the non-radiation field tumor caused by the immune response triggered by the local irradiated tumor and the combination of RT and immunotherapy to eliminate the tumor have become the focus of current research. As we all know, systemic RT can ablate the body′s immune system to lower the risk of xenotransplantation rejection in patients [1]. Conversely, a volume of studies have proved that local tumor irradiation can enhance the immune response, thereby allowing metastases away from the treatment site to be controlled [2]. The previous research indicated that the local RT of a tumor increased the expression level of major histocompatibility complex (MHC) class I molecules and improved the ability of presenting antigens of antigen presenting cells (APCs), the maturation of dendritic cells (DCs) was motivated, and the toxicity of nature killer (NK) cells and the tumor infiltration of CD8+ cytotoxic T lymphocytes (CTLs) were enhanced [3,4,5][3][4][5]. However, at the same time, ionizing radiation (IR) also mobilized some immunosuppressive cells, such as regulatory T (Treg) cells and M2 macrophage and myeloid-derived suppressor cells (MDSCs). The presence of these cells helped the tumor cells escape the supervision of the immune system, which greatly reduced the efficiency of IR treatment.

Targeting therapies against programmed cell death protein 1 (PD-1) and its ligand PD-L1, T-lymphocyte-associated antigen 4 (CTLA-4) has impelled the clinical treatment of cancer to move forward and has also been found to extend the response of RT on the antineoplastic function to the whole body through activating T cells. Building on this foundation, the combination of RT with immune checkpoints blockade (ICB) is increasingly used in the study of local RT and the RT-induced abscopal effect [6,7,8][6][7][8]. Monoclonal antibodies targeting CTLA-4 (ipilimumab), PD-1 (e.g., pembro-lizumab and nivolumab), and PD-L1 (e.g., avelumab, atezolizumab, and durvalumab) have been approved by the Food and Drug Administration of USA (FDA) in the treatment of various malignant tumors, such as melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and lymphoma [9]. Despite the great success of anti-CTLA-4 and anti-PD-1/PD-L1 therapy, due to the complex adjustment of anti-tumor immunity in the tumor microenvironment, only a small percentage of patients benefit from ICB. Therefore, a more in-depth exploration of ICB therapy is required.

2. Clinical Outcome on Combined Therapy

In many clinical cases, RT combined with ICB treatment has demonstrated considerable superiority in cancer patients. A 65-year-old woman was diagnosed with a metastatic mucosal melanoma which was found in early 2015, and her right buccal mucosa was discolored and diagnosed as a malignant melanoma, but the neck, chest, and abdomen were negative on CT. She underwent surgical resection in August 2015 and received adjuvant intensity modulated radiotherapy (IMRT) of 50 Gy in 20 fractions at the primary site between October and November 2015. Then, metastatic melanomas in her neck and lungs were found in June and July 2016 respectively. Starting from August 2016, she received four cycles of 200 mg pembrolizumab (anti-PD-1) (3 mg/kg) intravenously every three weeks, and then her neck was irradiated with 24 Gy in 3 fractions on days 0, 7, and 21, starting from 19 October 2016. The tumors in her neck had shrunk by 20% one week after the first radiotherapy, and then it was surprisingly found that the volume and number of lung lesions had subsided. During the period, the treatment performed well until July 2017, where two lung lesions were found to be growing, and then, with continued SBRT and 20 cycles of pembrolizumab administration, the overall disease remained stable [10].

In April 2004, a 33-year-old woman was diagnosed with cutaneous melanoma, and then the primary lesion was surgically removed. During this period, she was in good health. In 2008, a new lung nodule was discovered, and then standard chemotherapy was given. In February 2009, new lung nodules were surgically removed, and the pathological examination demonstrated that they were metastatic melanomas. In August 2009, a CT scan revealed a recurrent disease accompanied by a new pleural-based spinal mass and right hilar lymphadenopathy, which was followed by a total of 4 cycles of ipilimumab (anti-CTLA-4) (10 mg/kg) injection every three weeks. After that, ipilimumab treatment was continued, once every 12 weeks. By November 2010, her pleural-based paraspinal mass and new splenic lesions had increased, so a total of 28.5 Gy doses in 3 fractions of 6-MV photons were administrated to the paraspinal mass over 7 days. In February 2011, she received ipilimumab again. After 2 months, the lesions in the target irradiation field obviously regressed. What was even more surprising was that the lesions outside the irradiation sites (right hilar lymphadenopathy and splenic lesions) also regressed [11].

In another case, a 46-year-old man was diagnosed with advanced non-keratotic nasopharyngeal carcinoma in November 2010 and then underwent a combination of radiotherapy and chemotherapy (cisplatin and fluorouracil). However, in October 2011, he first developed distant and local recurrent disease and was subsequently diagnosed with bone metastasis. Immunotherapy with pembrolizumab began in January 2016, but after 6 months, the tumor continued to spread. Thus, the recurrent lesions were re-irradiated at a total dose of 45 Gy in 25 fractions over 6 weeks, pembrolizumab was suspended during radiotherapy. 7 weeks after completion of radiotherapy; pembrolizumab treatment was started again. In December 2016, re-staging of PET-CT and MRI was performed and revealed that all the tumor lesions had regressed significantly, companied by marked swelling of the lacrimal and salivary glands, which indicated an enhanced immune response. Subsequently, pembrolizumab was used for treatment once more, and the tumor further regressed, inflammation symptoms resolved, and local control was achieved without metastasis [12].

3. Conclusions and Perspectives

RT plus immunotherapy has become a trend to fight against tumors, which breaks through the confined cognition in traditional radiobiology that radiation causing the cytotoxicity on tumor cells mainly originates from the production of DNA DSBs. The mobilization and tumor infiltration of CD8+ T cells are important guarantees for radiation to keep functioning [13]. After irradiation, the damaged tumor cells release neo-antigens, DAMPs, and some chemokines, which further induce CD8+ T cells priming. Among those, the antigens presentation of APCs is particularly important to activate CD8+ T cells. The activated CD8+ T cells can migrate and infiltrate the metastases outside of the irradiated field when a certain amount is reached, resulting in the subsequent sustained effects of anti-tumor [14]. Nonetheless, CD8+ T cells are not to fight a lone battle, multiple immune cells are also involved. Noticeably, some of these immunosuppressive cells can baffle the anti-tumor immunity and abscopal effects stimulated by local RT to promote the survival of tumors, including M2 macrophages, MDSCs, immature DCs, and Treg [15,16,17][15][16][17]. There is a balance between immunosuppression and immunostimulation. Without intervention, the function of CD8+ T cells is insufficient to completely eradicate residual tumor cells in this equilibrium, causing tumor recurrence and confining the therapeutic efficacy of local RT [18,19][18][19].

However, the accession of immune checkpoint inhibitors (ICIs) upsets the balance via enhancing CD8+ T cells’ response. Immune checkpoints act as the “brake” of immune cells, which can invalidate the effector T cell response when specifically binding to its ligand, so that the cancerous cells can be free from immune surveillance and survive [7]. Therefore, local RT plus ICB induces a cascade reaction that magnifies and spreads the positive immune response continuously, and hence, it has become a promising treatment modality for both primary tumors and distant metastases in patients [20]. It has been clinically acknowledged that the anti-PD-1/PD-L1 axis and anti-CTLA-4 are remarkable for malignant tumors. In addition, although many new ICIs including anti-LAG-3, anti-TIGIT, and anti-TIM-3 are still in clinical trials, they also show unique advantages and huge potential and have been reported to reverse the exhaustion of T cells or NK cells to restore the lethality to tumors [21,22,23][21][22][23].

So, how does radiation affect the abscopal effects by modulating the immune cells? As we mentioned above, radiation increases antigen presentation by mediating the release of new antigens, increases surface antigens, and promotes the release of signaling molecules and inflammatory factors. Radiation-induced DNA damage also activates the cGAS-STING signaling pathway to release IFN. Both of these patterns are very critical for the activation and migration of T cells to distant sites to induce the abscopal effect. However, the radiation can also boost the expression of immune checkpoint ligands such as PD-L1, which makes the tumor escape the attack of the immune system. Thus, ICB application is of great significance for RT-induced abscopal effects and improves the cure of cancer. Although there have been extensive studies, the specific mechanism of radiation induced abscopal effect (RIAE) still needs to be further demonstrated.

Although the effect of ICIs is remarkable, its effect on certain tumors (such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers) is still limited. How to improve the efficacy of immune checkpoint inhibitors is a critical issue. Two strategies are currently being taken into consideration. The first strategy is to improve the response rate of ICIs in patients via specific predictive factors (PD-L1 expression, tumor mutation burden (TMB), and clinical characteristics). The other strategy is the combination of therapeutics with ICIs. Among them, the abscopal effect induced by RT combined with ICIs is frequently used to evaluate the efficacy of cancer immunotherapy. However, recent studies have also focused on the potential functions of some molecules, which can modify the immune microenvironment to up-regulate the proportion of immune-activated cells and down-regulate the immune-suppressive cells to improve the efficacy of cancer immunotherapy. The drugs include microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses [24].

As the superiority of RT combined immunotherapy is gradually emerging, some of the challenges faced cannot be neglected. The optimal dose and fractionation of RT, optimum administration point provided for the two therapeutic methods, and relevant biomarkers for tumor prediction are all variable factors for the efficacy of tumor treatment [25]. At the same time, the exploration of novel ICB and immune mechanisms and the collocation of different ICIs for RT to promote abscopal effects on more types of cancers are also issues that need to be considered in the future.

References

  1. Formenti, S.C.; Demaria, S. Combining radiotherapy and cancer immunotherapy: A paradigm shift. Journal of the National Cancer Institute 2013, 105, 256-265; DOI:10.1093/jnci/djs629Formenti, S.C.; Demaria, S. Combining radiotherapy and cancer immunotherapy: A paradigm shift. J. Natl. Cancer Inst. 2013, 105, 256–265.
  2. Herrera, F.G.; Bourhis, J.; Coukos, G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA: a cancer journal for clinicians 2017, 67, 65-85; DOI:10.3322/caac.21358Herrera, F.G.; Bourhis, J.; Coukos, G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J. Clin. 2017, 67, 65–85.
  3. 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. International journal of radiation oncology, biology, physics 2013, 86, 343-349; DOI:10.1016/j.ijrobp.2012.12.025Zeng, 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.
  4. Kaminski, J.M.; Shinohara, E.; Summers, J.B.; Niermann, K.J.; Morimoto, A.; Brousal, J. The controversial abscopal effect. Cancer treatment reviews 2005, 31, 159-172; DOI:10.1016/j.ctrv.2005.03.004Kaminski, J.M.; Shinohara, E.; Summers, J.B.; Niermann, K.J.; Morimoto, A.; Brousal, J. The controversial abscopal effect. Cancer Treat. Rev. 2005, 31, 159–172.
  5. Jarosz-Biej, M.; Smolarczyk, R.; Cichoń, T.; Kułach, N. Tumor microenvironment as a "game changer" in cancer radiotherapy. International journal of molecular sciences 2019, 20; DOI:10.3390/ijms20133212Jarosz-Biej, M.; Smolarczyk, R.; Cichoń, T.; Kułach, N. Tumor microenvironment as a "game changer" in cancer radiotherapy. Int. J. Mol. Sci. 2019, 20, 3212.
  6. Buchwald, Z.S.; Wynne, J.; Nasti, T.H.; Zhu, S.; Mourad, W.F.; Yan, W.; Gupta, S.; Khleif, S.N.; Khan, M.K. Radiation, immune checkpoint blockade and the abscopal effect: A critical review on timing, dose and fractionation. Frontiers in oncology 2018, 8, 612; DOI:10.3389/fonc.2018.00612Buchwald, Z.S.; Wynne, J.; Nasti, T.H.; Zhu, S.; Mourad, W.F.; Yan, W.; Gupta, S.; Khleif, S.N.; Khan, M.K. Radiation, immune checkpoint blockade and the abscopal effect: A critical review on timing, dose and fractionation. Front. Oncol. 2018, 8, 612.
  7. Thangamathesvaran, L.; Shah, R.; Verma, R.; Mahmoud, O. Immune checkpoint inhibitors and radiotherapy-concept and review of current literature. Annals of translational medicine 2018, 6, 155; DOI:10.21037/atm.2018.03.09Thangamathesvaran, L.; Shah, R.; Verma, R.; Mahmoud, O. Immune checkpoint inhibitors and radiotherapy-concept and review of current literature. Ann. Transl. Med. 2018, 6, 155.
  8. Liu, Y.; Dong, Y.; Kong, L.; Shi, F.; Zhu, H.; Yu, J. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. Journal of hematology & oncology 2018, 11, 104; DOI:10.1186/s13045-018-0647-8Liu, 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.
  9. Gadducci, A.; Guerrieri, M.E. Immune checkpoint inhibitors in gynecological cancers: Update of literature and perspectives of clinical research. Anticancer research 2017, 37, 5955-5965; DOI:10.21873/anticanres.12042Gadducci, A.; Guerrieri, M.E. Immune checkpoint inhibitors in gynecological cancers: Update of literature and perspectives of clinical research. Anticancer Res. 2017, 37, 5955–5965.
  10. Tsui, J.M.; Mihalcioiu, C.; Cury, F.L. Abscopal effect in a stage iv melanoma patient who progressed on pembrolizumab. Cureus 2018, 10, e2238; DOI:10.7759/cureus.2238Takeshima, T.; Chamoto, K.; Wakita, D.; Ohkuri, T.; Togashi, Y.; Shirato, H.; Kitamura, H.; Nishimura, T. Local radiation therapy inhibits tumor growth through the generation of tumor-specific ctl: Its potentiation by combination with th1 cell therapy. Cancer Res. 2010, 70, 2697–2706.
  11. 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. The New England journal of medicine 2012, 366, 925-931; DOI:10.1056/NEJMoa1112824Lee, Y.; Auh, S.L.; Wang, Y.; Burnette, B.; Wang, Y.; Meng, Y.; Beckett, M.; Sharma, R.; Chin, R.; Tu, T.; et al. Therapeutic effects of ablative radiation on local tumor require cd8+ t cells: Changing strategies for cancer treatment. Blood 2009, 114, 589–595.
  12. Finazzi, T.; Rordorf, T.; Ikenberg, K.; Huber, G.F.; Guckenberger, M.; Garcia Schueler, H.I. Radiotherapy-induced anti-tumor immune response and immune-related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti-pd-1 immunotherapy. BMC cancer 2018, 18, 395; DOI:10.1186/s12885-018-4295-8Lippitz, B.E.; Harris, R.A. A translational concept of immuno-radiobiology. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 2019, 140, 116–124.
  13. Lippitz, B.E.; Harris, R.A. A translational concept of immuno-radiobiology. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2019, 140, 116-124; DOI:10.1016/j.radonc.2019.06.001Mikhak, Z.; Strassner, J.P.; Luster, A.D. Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor ccr4. J. Exp. Med. 2013, 210, 1855–1869.
  14. Shiraishi, K.; Ishiwata, Y.; Nakagawa, K.; Yokochi, S.; Taruki, C.; Akuta, T.; Ohtomo, K.; Matsushima, K.; Tamatani, T.; Kanegasaki, S. Enhancement of antitumor radiation efficacy and consistent induction of the abscopal effect in mice by eci301, an active variant of macrophage inflammatory protein-1alpha. Clinical cancer research : an official journal of the American Association for Cancer Research 2008, 14, 1159-1166; DOI:10.1158/1078-0432.ccr-07-4485Akutsu, Y.; Matsubara, H.; Urashima, T.; Komatsu, A.; Sakata, H.; Nishimori, T.; Yoneyama, Y.; Hoshino, I.; Murakami, K.; Usui, A.; et al. Combination of direct intratumoral administration of dendritic cells and irradiation induces strong systemic antitumor effect mediated by grp94/gp96 against squamous cell carcinoma in mice. Int. J. Oncol. 2007, 31, 509–515.
  15. Kusmartsev, S.; Gabrilovich, D.I. Immature myeloid cells and cancer-associated immune suppression. Cancer immunology, immunotherapy : CII 2002, 51, 293-298; DOI:10.1007/s00262-002-0280-8Levy, A.; Chargari, C.; Marabelle, A.; Perfettini, J.L.; Magne, N.; Deutsch, E. Can immunostimulatory agents enhance the abscopal effect of radiotherapy? Eur. J. Cancer 2016, 62, 36–45.
  16. Mantovani, A.; Sica, A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Current opinion in immunology 2010, 22, 231-237; DOI:10.1016/j.coi.2010.01.009Ozpiskin, O.M.; Zhang, L.; Li, J.J. Immune targets in the tumor microenvironment treated by radiotherapy. Theranostics 2019, 9, 1215–1231.
  17. Hurwitz, A.A.; Watkins, S.K. Immune suppression in the tumor microenvironment: A role for dendritic cell-mediated tolerization of t cells. Cancer immunology, immunotherapy : CII 2012, 61, 289-293; DOI:10.1007/s00262-011-1181-5Hu, Z.I.; McArthur, H.L.; Ho, A.Y. The abscopal effect of radiation therapy: What is it and how can we use it in breast cancer? Curr. Breast Cancer Rep. 2017, 9, 45–51.
  18. Lee, Y.; Auh, S.L.; Wang, Y.; Burnette, B.; Wang, Y.; Meng, Y.; Beckett, M.; Sharma, R.; Chin, R.; Tu, T., et al. Therapeutic effects of ablative radiation on local tumor require cd8+ t cells: Changing strategies for cancer treatment. Blood 2009, 114, 589-595; DOI:10.1182/blood-2009-02-206870Demaria, S.; Ng, B.; Devitt, M.L.; Babb, J.S.; Kawashima, N.; Liebes, L.; Formenti, S.C. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 2004, 58, 862–870.
  19. Michelle Xu, M.; Pu, Y.; Weichselbaum, R.R.; Fu, Y.X. Integrating conventional and antibody-based targeted anticancer treatment into immunotherapy. Oncogene 2017, 36, 585-592; DOI:10.1038/onc.2016.231Matsumura, S.; Demaria, S. Up-regulation of the pro-inflammatory chemokine cxcl16 is a common response of tumor cells to ionizing radiation. Radiat. Res. 2010, 173, 418–425.
  20. Marshall, H.T.; Djamgoz, M.B.A. Immuno-oncology: Emerging targets and combination therapies. Frontiers in oncology 2018, 8, 315; DOI:10.3389/fonc.2018.00315Chakraborty, M.; Abrams, S.I.; Camphausen, K.; Liu, K.; Scott, T.; Coleman, C.N.; Hodge, J.W. Irradiation of tumor cells up-regulates fas and enhances ctl lytic activity and ctl adoptive immunotherapy. J. Immunol. (Baltim. Md. 1950) 2003, 170, 6338–6347.
  21. Wang, J.; Sanmamed, M.F.; Datar, I.; Su, T.T.; Ji, L.; Sun, J.; Chen, L.; Chen, Y.; Zhu, G.; Yin, W., et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of lag-3. Cell 2019, 176, 334-347.e312; DOI:10.1016/j.cell.2018.11.010Garnett, 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.
  22. Zhang, Q.; Bi, J. Blockade of the checkpoint receptor tigit prevents nk cell exhaustion and elicits potent anti-tumor immunity. 2018, 19, 723-732; DOI:10.1038/s41590-018-0132-0Hallahan, D.; Kuchibhotla, J.; Wyble, C. Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium. Cancer Res. 1996, 56, 5150–5155.
  23. Du, W.; Yang, M.; Turner, A.; Xu, C.; Ferris, R.L.; Huang, J.; Kane, L.P.; Lu, B. Tim-3 as a target for cancer immunotherapy and mechanisms of action. International journal of molecular sciences 2017, 18; DOI:10.3390/ijms18030645Gao, H.; Dong, Z.; Gong, X.; Dong, J.; Zhang, Y.; Wei, W.; Wang, R.; Jin, S. Effects of various radiation doses on induced t-helper cell differentiation and related cytokine secretion. J. Radiat. Res. 2018, 59, 395–403.
  24. Longo, V.; Brunetti, O. Strategies to improve cancer immune checkpoint inhibitors efficacy, other than abscopal effect: A systematic review. 2019, 11; DOI:10.3390/cancers11040539Adair, P.; Kim, Y.C.; Pratt, K.P.; Scott, D.W. Avidity of human t cell receptor engineered cd4(+) t cells drives t-helper differentiation fate. Cell. Immunol. 2016, 299, 30–41.
  25. Wani, S.Q.; Dar, I.A.; Khan, T.; Lone, M.M.; Afroz, F. Radiation therapy and its effects beyond the primary target: An abscopal effect. Cureus 2019, 11, e4100; DOI:10.7759/cureus.4100Agnello, D.; Lankford, C.S.; Bream, J.; Morinobu, A.; Gadina, M.; O’Shea, J.J.; Frucht, D.M. Cytokines and transcription factors that regulate t helper cell differentiation: New players and new insights. J. Clin. Immunol. 2003, 23, 147–161.
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