You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1
Gary Hannon
 -- 1450 2023-05-04 16:08:55 |
2 format correct
Conner Chen
 Meta information modification 1450 2023-05-06 04:38:15 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Hannon, G.; Lesch, M.L.; Gerber, S.A. Immunogenic Cell Death by Radiation. Encyclopedia. Available online: https://encyclopedia.pub/entry/43778 (accessed on 09 July 2025).
Hannon G, Lesch ML, Gerber SA. Immunogenic Cell Death by Radiation. Encyclopedia. Available at: https://encyclopedia.pub/entry/43778. Accessed July 09, 2025.
Hannon, Gary, Maggie L. Lesch, Scott A. Gerber. "Immunogenic Cell Death by Radiation" Encyclopedia, https://encyclopedia.pub/entry/43778 (accessed July 09, 2025).
Hannon, G., Lesch, M.L., & Gerber, S.A. (2023, May 04). Immunogenic Cell Death by Radiation. In Encyclopedia. https://encyclopedia.pub/entry/43778
Hannon, Gary, et al. "Immunogenic Cell Death by Radiation." Encyclopedia. Web. 04 May, 2023.
Immunogenic Cell Death by Radiation
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms24087359

Ionizing radiation (IR) is used to treat 50% of cancers. While the cytotoxic effects related to DNA damage with IR have been known since the early 20th century, the role of the immune system in the treatment response is still yet to be fully determined. IR can induce immunogenic cell death (ICD), which activates innate and adaptive immunity against the cancer.

radiation cancer immunity immunotherapies

1. Introduction

Ionizing radiation (IR) is a prevalent non-surgical intervention for achieving cures in cancer [1]. Approximately 50% of cancers are treated with some form of IR [2][3], and it is estimated that this contributes to 40% of cures [4][5]. While the cytotoxic effects of IR on cancer were first appreciated in the early 20th century, following Röntgen’s discovery of X-rays in 1895 [6], the complex mechanisms by which the tumor microenvironment (TME) is altered following IR are still being elucidated today [7][8][9].
Notably, the immune modulatory potential of IR has gained particular interest. Cancers exploit naturally occurring immunosuppressive mechanisms to facilitate their growth and metastasis, and many reports show that IR is capable of reprogramming the TME to alleviate this suppression and even achieve abscopal effects in rare cases [10]. Following IR exposure, cancer cells undergo an immunogenic form of cell death which results in antigen presenting cell (APC) activation and maturation, leading to eventual cytotoxic T cell responses specific to the tumor [11]. Interestingly, multiple reports now describe that an intact immune system is essential to the efficacy of IR [12][13][14][15].
While the large body of evidence for the immune stimulatory effects of IR is certainly convincing, numerous reports also show that IR can induce a wound healing response characterized by tumor-associated macrophage (TAM), myeloid-derived suppressor cell (MDSC) and regulatory T cell (Treg) recruitment to tumors [16][17]. These cells dampen anti-tumor immune responses and initiate angiogenic processes, augmenting tumor growth and expansion [18][19]. Moreover, a higher number of these cells correlate with poorer prognosis in many cancers [20][21]. Hence, a dichotomy exists with this therapy where both immune stimulatory and immunosuppressive effects occur, often simultaneously [16].
Navigating this literature can be challenging, as the immunological responses are highly dynamic and can vary depending on the TME in question and the IR protocol used [22][23][24][25][26].

2. Radiation Induced Immunogenic Cell Death

Immediately following radiation, DNA is damaged via direct ionization or indirectly through the action of free radicals (such as reactive oxygen species; ROS) generated when radiation ionizes water molecules or biomolecules in cells. Cells are composed of 80% water, and it has been estimated that the indirect effects of radiation account for 60% of the total cellular damage accumulated [27]. This DNA damage occurs in the form of single-strand and double-strand breaks that are sensed by ataxia telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases, which in turn activate DNA repair mechanisms in the cells. However, if the damage accumulated exceeds cellular repair capabilities, the cells will undergo cell death or senescence [28].

2.1. Senescence and Cell Death

In the case of senescence, the cell terminates division processes through p53/p21 and p16/RB1 signaling [29]. The cell remains viable but undergoes arrest to prevent further damage and outgrowth of mutated cells. For cell death, on the other hand, several death pathways can occur depending on the extent of the damage. Lower, recoverable levels of damage are associated with programmed mechanisms of death such as apoptosis and autophagy, whereas higher levels evoke irreparable damage resulting in necrosis [30]. Typically, necrosis has been defined as immunogenic and apoptosis has been defined as immune silent; however, it is now known that all forms of cell death possess some level of immunogenicity [31]. ICD broadly refers to a form of cell death that involves the release of damage-associated molecular patterns (DAMPs), chemokines, cytokines and tumor antigens that prime APCs and instigate adaptive immune responses (Figure 1) [11]. IR has been shown to induce these markers of ICD (calreticulin, high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP)) in a dose-dependent manner (ranging from 0 to 100 Gy) [32][33].

2.2. Damage-Associated Molecular Patterns

Following IR-induced cellular damage, DAMPs such as calreticulin, heat shock protein-70 (HSP70), HMGB1 and ATP, which are normally endogenous in nature, get released by dying cells to facilitate phagocytosis [31][34]. Calreticulin and HSP70 are endoplasmic reticulum (ER) molecular chaperones that translocate to the cell membrane following cellular damage. Once expressed on the surface, they can bind to CD91 expressed on APCs and act as an ‘eat me’ signal for the dying cell [35][36]. Additionally, the HSP family of proteins may also present carried tumor antigens to APCs directly [37]. HMGB1 is a nuclear protein that governs chromosomal structure and function. Although its main function is to act as a DNA chaperone, it can be passively released during cell death and bind to toll-like receptors (mainly TLR4) on APCs to augment phagocytosis and antigen processing via MyD88 signaling [38][39]. ATP is somewhat different, as it requires autophagy for its active release from dying cells [40]. Autophagy is a stress response that initiates the molecular recycling of cellular organelles and cytoplasmic proteins under hostile conditions. Following extracellular release, ATP functions as a chemoattractant for dendritic cells (DC) by binding to purinergic receptors [41][42]. Conversely, although DAMPs generation in the tumor is an important immune activator, studies assessing correlations between the levels and overall outcome have generated contested results [43][44]. It is likely that elevating DAMPs alone is not enough to elicit measurable benefits to radiation, but many factors of the tumor microenvironment (TME) are critical when considering this response.

2.3. Cytokine Release

The release of cytokines following IR is a massive field of research, with a large volume of work being published on various cytokines including IFN-γ [45], IL-1β [46], TNF-α [47], IL-6 [48] and TGF-β [49]. Among these, the Type-I interferons (IFN) have proven particularly prominent in recent times. Type-I IFN is a family of pro-inflammatory cytokines heavily involved in the response to viral infection. They are also pivotal for anti-tumor immune responses following IR, primarily through DC cross-priming [50][51][52]. IR induces Type-I IFN expression (IFN-α and IFN-β, in particular) through multiple endogenous nucleic acid sensing pathways following the release of double-stranded DNA and RNA into the cytosol of damaged cells [53]. Cyclic GMP-AMP synthase (cGAS) is an enzyme that catalyzes the formation of cyclic GMP-AMP (cGAMP) when it recognizes cytosolic DNA. cGAMP then binds to and activates STING (stimulator of interferon genes) in the ER [54][55]. STING is an adaptor molecule, and its activation leads to downstream Type-I IFN expression [56]. Notably, STING also activates NF-κB signaling, inducing a vast array of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 [57][58]. DNA and RNA are also capable of triggering Type-I IFN release through endosomal TLRs (TLR9 for DNA; TLR3, 7 and 8 for RNA) and their adaptor molecules MyD88 or TRIF [59][60]. Cytosolic RNA can additionally be detected by RIG-I-like receptors (RLR) and induce IFN-β expression via the mitochondrial adaptor protein MAVS [61]. Regardless of the pathway involved, however, multiple reports have demonstrated that Type-I IFN production is essential to IR efficacy. When this pathway is inhibited, tumor burden is similar to unirradiated controls, and it has been shown that CD8+ T cell cytotoxic function in these tumors is impaired [52][62][63][64].

2.4. Chemokine Release

IR leads to an influx of immune cells into the TME through chemokine gradients as a form of damage control. Chemokines are produced by multiple cells in the TME and bind to their cognate receptors in an autocrine or paracrine fashion [65]. CCL2 is upregulated in tumors following IR, and this facilitates CCR2+ monocyte and Treg recruitment to tumors [66][67]. Recent research points towards STING-dependent expression of CCL2, suggesting this pathway is a double-edged sword in IR treatment [68]. On one hand, there is Type-I IFN expression that fosters anti-tumor immunity; on the other, there is an influx of immunosuppressive monocytes and Tregs that evoke radioresistance and tumor growth [69]. Another chemokine ligand produced downstream of the cGAS-STING pathway following IR is CCL5 [70]. CCL5 is also involved in trafficking monocytes to the tumor utilizing the CCR5 receptor, in particular [70][71]. While the receptors for these chemokines are also expressed on T cells, higher levels of CCL5 expression are typically associated with poorer outcomes in cancer [72]. This suggests that the immunosuppressive infiltrate dominates any potential anti-tumor immune responses driven by chemokine signaling following IR. Overall, the broad topic of chemokine expression following radiation is highly complex, influencing both pro- and anti-tumor immune cell types and varying based on the tumor, IR dose and time-point measured [73][74][75]. It has been shown, however, that inhibiting CCR2/CCR5 signaling can sensitize tumors to IR [71].
Ijms 24 07359 g001
Figure 1. Immunogenic cell death elicited by IR. ICD induced by IR is marked by the release of DAMPs (HMGB1, double-stranded DNA and RNA, HSP70, ATP and calreticulin (CRT)), Type I IFN (IFN-α and IFN-β) through cGAS-STING signaling and other cytokines (TNF-α, IL-1ß and IL-6) and chemokines (CCL2 and CCL5) through STING-induced NF-κB activation. Broken lines indicate movement and continuous lines represent the production of the given target.

References

  1. Barnett, G.C.; West, C.M.; Dunning, A.M.; Elliott, R.M.; Coles, C.E.; Pharoah, P.D.; Burnet, N.G. Normal tissue reactions to radiotherapy: Towards tailoring treatment dose by genotype. Nat. Rev. Cancer 2009, 9, 134–142.
  2. Delaney, G.; Jacob, S.; Featherstone, C.; Barton, M. The role of radiotherapy in cancer treatment: Estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer 2005, 104, 1129–1137.
  3. Barton, M.B.; Jacob, S.; Shafiq, J.; Wong, K.; Thompson, S.R.; Hanna, T.P.; Delaney, G.P. Estimating the demand for radiotherapy from the evidence: A review of changes from 2003 to 2012. Radiother. Oncol. 2014, 112, 140–144.
  4. Department of Health. Radiotherapy Services in England. 2012. Available online: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/213151/Radiotherapy-Services-in-England-2012.pdf (accessed on 12 April 2023).
  5. Sharma, R.A.; Plummer, R.; Stock, J.K.; Greenhalgh, T.A.; Ataman, O.; Kelly, S.; Clay, R.; Adams, R.A.; Baird, R.D.; Billingham, L.; et al. Clinical development of new drug–radiotherapy combinations. Nat. Rev. Clin. Oncol. 2016, 13, 627–642.
  6. Bernier, J.; Hall, E.J.; Giaccia, A. Radiation oncology: A century of achievements. Nat. Rev. Cancer 2004, 4, 737–747.
  7. 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.
  8. Menon, H.; Ramapriyan, R.; Cushman, T.R.; Verma, V.; Kim, H.H.; Schoenhals, J.E.; Atalar, C.; Selek, U.; Chun, S.G.; Chang, J.Y.; et al. Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment. Front. Immunol. 2019, 10, 193.
  9. Ansems, M.; Span, P.N. The tumor microenvironment and radiotherapy response; a central role for cancer-associated fibroblasts. Clin. Transl. Radiat. Oncol. 2020, 22, 90–97.
  10. Craig, D.J.; Nanavaty, N.S.; Devanaboyina, M.; Stanbery, L.; Hamouda, D.; Edelman, G.; Dworkin, L.; Nemunaitis, J.J. The abscopal effect of radiation therapy. Future Oncol. 2021, 17, 1683–1694.
  11. Zhu, M.; Yang, M.; Zhang, J.; Yin, Y.; Fan, X.; Zhang, Y.; Qin, S.; Zhang, H.; Yu, F. Immunogenic Cell Death Induction by Ionizing Radiation. Front. Immunol. 2021, 12, 5361.
  12. Tseng, Y.D.; Nguyen, M.H.; Baker, K.; Cook, M.; Redman, M.; Lachance, K.; Bhatia, S.; Liao, J.J.; Apisarnthanarax, S.; Nghiem, P.T.; et al. Effect of Patient Immune Status on the Efficacy of Radiation Therapy and Recurrence-Free Survival Among 805 Patients With Merkel Cell Carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2018, 102, 330–339.
  13. Gerber, S.A.; Sedlacek, A.L.; Cron, K.R.; Murphy, S.P.; Frelinger, J.G.; Lord, E.M. IFN-γ mediates the antitumor effects of radiation therapy in a murine colon tumor. Am. J. Pathol. 2013, 182, 2345–2354.
  14. Stone, H.B.; Peters, L.J.; Milas, L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J. Natl. Cancer Inst. 1979, 63, 1229–1235.
  15. Takeshima, 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.
  16. Lin, L.; Kane, N.; Kobayashi, N.; Kono, E.A.; Yamashiro, J.M.; Nickols, N.G.; Reiter, R.E. High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors. Clinical. Cancer Res. 2021, 27, 1505–1515.
  17. Muroyama, Y.; Nirschl, T.R.; Kochel, C.M.; Lopez-Bujanda, Z.; Theodros, D.; Mao, W.; Carrera-Haro, M.A.; Ghasemzadeh, A.; Marciscano, A.E.; Velarde, E.; et al. Stereotactic Radiotherapy Increases Functionally Suppressive Regulatory T Cells in the Tumor Microenvironment. Cancer Immunol. Res. 2017, 5, 992–1004.
  18. Lindau, D.; Gielen, P.; Kroesen, M.; Wesseling, P.; Adema, G.J. The immunosuppressive tumour network: Myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology 2013, 138, 105–115.
  19. Haist, M.; Stege, H.; Grabbe, S.; Bros, M. The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment. Cancers 2021, 13, 210.
  20. Li, K.; Shi, H.; Zhang, B.; Ou, X.; Ma, Q.; Chen, Y.; Shu, P.; Li, D.; Wang, Y. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer. Signal Transduct. Target. Ther. 2021, 6, 362.
  21. Saleh, R.; Elkord, E. FoxP3+ T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett. 2020, 490, 174–185.
  22. Lai, J.-Z.; Zhu, Y.-Y.; Liu, Y.; Zhou, L.-L.; Hu, L.; Chen, L.; Zhang, Q.-Y. Abscopal Effects of Local Radiotherapy Are Dependent on Tumor Immunogenicity. Front. Oncol. 2021, 11, 188.
  23. 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.
  24. 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.
  25. Demaria, S.; Guha, C.; Schoenfeld, J.; Morris, Z.; Monjazeb, A.; Sikora, A.; Crittenden, M.; Shiao, S.; Khleif, S.; Gupta, S.; et al. Radiation dose and fraction in immunotherapy: One-size regimen does not fit all settings, so how does one choose? J. Immunother. Cancer 2021, 9, e002038.
  26. Chen, J.; Liu, X.; Zeng, Z.; Li, J.; Luo, Y.; Sun, W.; Gong, Y.; Zhang, J.; Wu, Q.; Xie, C. Immunomodulation of NK Cells by Ionizing Radiation. Front Oncol. 2020, 10, 874.
  27. Baskar, R.; Dai, J.; Wenlong, N.; Yeo, R.; Yeoh, K.W. Biological response of cancer cells to radiation treatment. Front Mol. Biosci. 2014, 1, 24.
  28. Matt, S.; Hofmann, T.G. The DNA damage-induced cell death response: A roadmap to kill cancer cells. Cell. Mol. Life Sci. 2016, 73, 2829–2850.
  29. Childs, B.G.; Baker, D.J.; Kirkland, J.L.; Campisi, J.; van Deursen, J.M. Senescence and apoptosis: Dueling or complementary cell fates? EMBO Rep. 2014, 15, 1139–1153.
  30. Adjemian, S.; Oltean, T.; Martens, S.; Wiernicki, B.; Goossens, V.; Vanden Berghe, T.; Cappe, B.; Ladik, M.; Riquet, F.B.; Heyndrickx, L.; et al. Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death. Cell Death Dis. 2020, 11, 1003.
  31. 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.
  32. 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.
  33. 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.
  34. Ye, J.; Mills, B.N.; Zhao, T.; Han, B.J.; Murphy, J.D.; Patel, A.P.; Johnston, C.J.; Lord, E.M.; Belt, B.A.; Linehan, D.C.; et al. Assessing the Magnitude of Immunogenic Cell Death Following Chemotherapy and Irradiation Reveals a New Strategy to Treat Pancreatic Cancer. Cancer Immunol. Res. 2020, 8, 94–107.
  35. Basu, S.; Binder, R.J.; Ramalingam, T.; Srivastava, P.K. CD91 Is a Common Receptor for Heat Shock Proteins gp96, hsp90, hsp70, and Calreticulin. Immunity 2001, 14, 303–313.
  36. Gardai, S.J.; McPhillips, K.A.; Frasch, S.C.; Janssen, W.J.; Starefeldt, A.; Murphy-Ullrich, J.E.; Bratton, D.L.; Oldenborg, P.A.; Michalak, M.; Henson, P.M. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 2005, 123, 321–334.
  37. Multhoff, G.; Pockley, A.G.; Schmid, T.E.; Schilling, D. The role of heat shock protein 70 (Hsp70) in radiation-induced immunomodulation. Cancer Lett. 2015, 368, 179–184.
  38. Kim, S.; Kim, S.Y.; Pribis, J.P.; Lotze, M.; Mollen, K.P.; Shapiro, R.; Loughran, P.; Scott, M.J.; Billiar, T.R. Signaling of high mobility group box 1 (HMGB1) through toll-like receptor 4 in macrophages requires CD14. Mol. Med. 2013, 19, 88–98.
  39. Apetoh, L.; Ghiringhelli, F.; Tesniere, A.; Obeid, M.; Ortiz, C.; Criollo, A.; Mignot, G.; Maiuri, M.C.; Ullrich, E.; Saulnier, P.; et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 2007, 13, 1050–1059.
  40. Martins, I.; Wang, Y.; Michaud, M.; Ma, Y.; Sukkurwala, A.Q.; Shen, S.; Kepp, O.; Métivier, D.; Galluzzi, L.; Perfettini, J.L.; et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 2014, 21, 79–91.
  41. Kojima, S.; Ohshima, Y.; Nakatsukasa, H.; Tsukimoto, M. Role of ATP as a Key Signaling Molecule Mediating Radiation-Induced Biological Effects. Dose Response 2017, 15, 1559325817690638.
  42. Ko, A.; Kanehisa, A.; Martins, I.; Senovilla, L.; Chargari, C.; Dugue, D.; Mariño, G.; Kepp, O.; Michaud, M.; Perfettini, J.L.; et al. Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling. Cell Death Differ. 2014, 21, 92–99.
  43. Vaes, R.D.W.; Hendriks, L.E.L.; Vooijs, M.; De Ruysscher, D. Biomarkers of Radiotherapy-Induced Immunogenic Cell Death. Cells 2021, 10, 930.
  44. Fucikova, J.; Moserova, I.; Urbanova, L.; Bezu, L.; Kepp, O.; Cremer, I.; Salek, C.; Strnad, P.; Kroemer, G.; Galluzzi, L.; et al. Prognostic and Predictive Value of DAMPs and DAMP-Associated Processes in Cancer. Front. Immunol. 2015, 6, 402.
  45. Lugade, A.A.; Sorensen, E.W.; Gerber, S.A.; Moran, J.P.; Frelinger, J.G.; Lord, E.M. Radiation-Induced IFN-γ Production within the Tumor Microenvironment Influences Antitumor Immunity. J. Immunol. 2008, 180, 3132–3139.
  46. Liu, W.; Ding, I.; Chen, K.; Olschowka, J.; Xu, J.; Hu, D.; Morrow, G.R.; Okunieff, P. Interleukin 1β (IL1B) Signaling Is a Critical Component of Radiation-Induced Skin Fibrosis. Radiat. Res. 2006, 165, 181–191.
  47. Rübe, C.E.; Wilfert, F.; Uthe, D.; Schmid, K.W.; Knoop, R.; Willich, N.; Schuck, A.; Rübe, C. Modulation of radiation-induced tumour necrosis factor alpha (TNF-alpha) expression in the lung tissue by pentoxifylline. Radiother. Oncol. 2002, 64, 177–187.
  48. Matsuoka, Y.; Nakayama, H.; Yoshida, R.; Hirosue, A.; Nagata, M.; Tanaka, T.; Kawahara, K.; Sakata, J.; Arita, H.; Nakashima, H.; et al. IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma. Br. J. Cancer 2016, 115, 1234–1244.
  49. Farhood, B.; Khodamoradi, E.; Hoseini-Ghahfarokhi, M.; Motevaseli, E.; Mirtavoos-Mahyari, H.; Eleojo Musa, A.; Najafi, M. TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury. Pharmacol. Res. 2020, 155, 104745.
  50. Yu, R.; Zhu, B.; Chen, D. Type I interferon-mediated tumor immunity and its role in immunotherapy. Cell. Mol. Life Sci. 2022, 79, 191.
  51. Parker, B.S.; Rautela, J.; Hertzog, P.J. Antitumour actions of interferons: Implications for cancer therapy. Nat. Rev. Cancer 2016, 16, 131–144.
  52. 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.
  53. Zhang, F.; Manna, S.; Pop, L.M.; Chen, Z.J.; Fu, Y.X.; Hannan, R. Type I Interferon Response in Radiation-Induced Anti-Tumor Immunity. Semin. Radiat. Oncol. 2020, 30, 129–138.
  54. Deng, L.; Liang, H.; Xu, M.; Yang, X.; Burnette, B.; Arina, A.; Li, X.-D.; Mauceri, H.; Beckett, M.; Darga, T.; et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity 2014, 41, 843–852.
  55. Wu, J.; Sun, L.; Chen, X.; Du, F.; Shi, H.; Chen, C.; Chen, Z.J. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 2013, 339, 826–830.
  56. Ishikawa, H.; Barber, G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 2008, 455, 674–678.
  57. Abe, T.; Barber, G.N. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-κB activation through TBK1. J. Virol. 2014, 88, 5328–5341.
  58. Dunphy, G.; Flannery, S.M.; Almine, J.F.; Connolly, D.J.; Paulus, C.; Jønsson, K.L.; Jakobsen, M.R.; Nevels, M.M.; Bowie, A.G.; Unterholzner, L. Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage. Mol. Cell 2018, 71, 745–760.e745.
  59. Kawai, T.; Sato, S.; Ishii, K.J.; Coban, C.; Hemmi, H.; Yamamoto, M.; Terai, K.; Matsuda, M.; Inoue, J.-i.; Uematsu, S.; et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 2004, 5, 1061–1068.
  60. Chow, K.T., Jr.; Gale, M.; Loo, Y.-M. RIG-I and Other RNA Sensors in Antiviral Immunity. Annu. Rev. Immunol. 2018, 36, 667–694.
  61. Ranoa, D.R.E.; Parekh, A.D.; Pitroda, S.P.; Huang, X.; Darga, T.; Wong, A.C.; Huang, L.; Andrade, J.; Staley, J.P.; Satoh, T.; et al. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs. Oncotarget 2016, 7, 26496–26515.
  62. Goedegebuure, R.S.A.; Kleibeuker, E.A.; Buffa, F.M.; Castricum, K.C.M.; Haider, S.; Schulkens, I.A.; Ten Kroode, L.; van den Berg, J.; Jacobs, M.; van Berkel, A.M.; et al. Interferon- and STING-independent induction of type I interferon stimulated genes during fractionated irradiation. J. Exp. Clin. Cancer Res. 2021, 40, 161.
  63. Yang, K.; Hou, Y.; Zhang, Y.; Liang, H.; Sharma, A.; Zheng, W.; Wang, L.; Torres, R.; Tatebe, K.; Chmura, S.J.; et al. Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation. J. Exp. Med. 2021, 218, 1915.
  64. Lim, J.Y.H.; Gerber, S.A.; Murphy, S.P.; Lord, E.M. Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol. Immunother. 2014, 63, 259–271.
  65. Vilgelm, A.E.; Richmond, A. Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy. Front. Immunol. 2019, 10, 333.
  66. Kalbasi, A.; Komar, C.; Tooker, G.M.; Liu, M.; Lee, J.W.; Gladney, W.L.; Ben-Josef, E.; Beatty, G.L. Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma. Clin. Cancer Res. 2017, 23, 137–148.
  67. Mondini, M.; Loyher, P.L.; Hamon, P.; Gerbé de Thoré, M.; Laviron, M.; Berthelot, K.; Clémenson, C.; Salomon, B.L.; Combadière, C.; Deutsch, E.; et al. CCR2-Dependent Recruitment of Tregs and Monocytes Following Radiotherapy Is Associated with TNFα-Mediated Resistance. Cancer Immunol. Res. 2019, 7, 376–387.
  68. 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.
  69. Budhwani, M.; Mazzieri, R.; Dolcetti, R. Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance. Front Oncol. 2018, 8, 322.
  70. Zheng, Z.; Jia, S.; Shao, C.; Shi, Y. Irradiation induces cancer lung metastasis through activation of the cGAS–STING–CCL5 pathway in mesenchymal stromal cells. Cell Death Dis. 2020, 11, 326.
  71. Connolly, K.A.; Belt, B.A.; Figueroa, N.M.; Murthy, A.; Patel, A.; Kim, M.; Lord, E.M.; Linehan, D.C.; Gerber, S.A. Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget 2016, 7, 86522–86535.
  72. Xu, M.; Wang, Y.; Xia, R.; Wei, Y.; Wei, X. Role of the CCL2-CCR2 signalling axis in cancer: Mechanisms and therapeutic targeting. Cell. Prolif. 2021, 54, e13115.
  73. Manning, G.; Tichý, A.; Sirák, I.; Badie, C. Radiotherapy-Associated Long-term Modification of Expression of the Inflammatory Biomarker Genes ARG1, BCL2L1, and MYC. Front. Immunol. 2017, 8, 412.
  74. Wolff, H.A.; Rolke, D.; Rave-Fränk, M.; Schirmer, M.; Eicheler, W.; Doerfler, A.; Hille, A.; Hess, C.F.; Matthias, C.; Rödel, R.M.W.; et al. Analysis of chemokine and chemokine receptor expression in squamous cell carcinoma of the head and neck (SCCHN) cell lines. Radiat. Environ. Biophys. 2011, 50, 145–154.
  75. Wang, L.; Jiang, J.; Chen, Y.; Jia, Q.; Chu, Q. The roles of CC chemokines in response to radiation. Radiat. Oncol. 2022, 17, 63.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Immunology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Gary Hannon
,
Maggie L. Lesch
,
Scott A. Gerber
View Times: 476
Revisions: 2 times (View History)
Update Date: 06 May 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Academic Video Service
    Feedback