Abstract:As early as the 20th century, it has been observed that radiotherapy (RT), as a local therapy, can activate the adaptive immune system, resulting in spontaneous regression of tumors out of the radiation field, which is known as "abscopal effect". Although the occurrence of abscopal effect is still rare, with the gradual increase in the application of immunotherapy, more and more clinical cases of abscopal effect have been reported. Increasing attention has been paid to the therapeutic potential of RT in inducing systemic anti-tumor response. Especially, the combination of RT and immunotherapy enhances the research value of abscopal effect. However, its mechanism has not been fully elucidated, and the optimal timing, dose and fractionation of RT are also under study. How to classify the beneficiary groups is also a key issue. In this article, the history of abscopal effect, and the role of RT and immunotherapy in this phenomenon were briefly introduced, and the existing controversies in clinical application were illustrated, aiming to clarify the direction of current research and development and open a new chapter for tumor treatment in a short period of time.
Zhang Lu,Liu Hongbo,Ding Xiao et al. The roles and clinical controversies of radiotherapy and immunotherapy in abscopal effect[J]. Chinese Journal of Radiation Oncology, 2023, 32(5): 470-475.
[1] McCulloch HD. On the analogy between spontaneous recoveries from cancer and the specific immunity induced by X ray irradiations of the lymphatic glands involved[J]. Br Med J, 1908,2(2494):1146-1148. DOI: 10.1136/bmj.2.2494.1146. [2] Brix N, Tiefenthaller A, Anders H, et al.Abscopal, immunological effects of radiotherapy: narrowing the gap between clinical and preclinical experiences[J]. Immunol Rev, 2017,280(1):249-279. DOI: 10.1111/imr.12573. [3] Mole RH. Whole body irradiation; radiobiology or medicine?[J].Br J Radiol,1953,26(305):234-241.DOI: 10.1259/0007-1285-26-305-234. [4] Demaria S, Ng B, Devitt ML, et al.Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated[J]. Int J Radiat Oncol Biol Phys, 2004,58(3):862-870. DOI: 10.1016/j.ijrobp.2003.09.012. [5] Dagoglu N, Karaman S, Caglar HB, et al.Abscopal effect of radiotherapy in the immunotherapy era: systematic review of reported cases[J]. Cureus, 2019,11(2):e4103. DOI: 10.7759/cureus.4103. [6] Lei X, Lei Y, Li JK, et al.Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy[J]. Cancer Lett, 2020,470:126-133. DOI: 10.1016/j.canlet.2019.11.009. [7] Hsieh CS, Lee HM, Lio CW.Selection of regulatory T cells in the thymus[J]. Nat Rev Immunol, 2012,12(3):157-167. DOI: 10.1038/nri3155. [8] Gabrilovich DI.Myeloid-derived suppressor cells[J]. Cancer Immunol Res, 2017,5(1):3-8. DOI: 10.1158/2326-6066.CIR-16-0297. [9] Garrido F, Aptsiauri N.Cancer immune escape: MHC expression in primary tumours versus metastases[J]. Immunology, 2019,158(4):255-266. DOI: 10.1111/imm.13114. [10] Curtin JF, Liu NY, Candolfi M, et al.HMGB1 mediates endogenous TLR2 activation and brain tumor regression[J]. PLoS Med, 2009,6(1):e10. DOI: 10.1371/journal.pmed.1000010. [11] El-Saghire H, Michaux A, Thierens H, et al.Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes[J]. Int J Mol Med, 2013,32(6):1407-1414. DOI: 10.3892/ijmm.2013.1514. [12] Portella L, Scala S.Ionizing radiation effects on the tumor microenvironment[J]. Semin Oncol, 2019,46(3):254-260. DOI: 10.1053/j.seminoncol.2019.07.003. [13] Ding Q, Lu PP, Xia YJ, et al.CXCL9: evidence and contradictions for its role in tumor progression[J]. Cancer Med, 2016,5(11):3246-3259. DOI: 10.1002/cam4.934. [14] Tokunaga R, Zhang W, Naseem M, et al.CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation- a target for novel cancer therapy[J]. Cancer Treat Rev, 2018,63:40-47. DOI: 10.1016/j.ctrv.2017.11.007. [15] Matsumura S, Wang B, Kawashima N, et al.Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells[J]. J Immunol, 2008,181(5):3099-3107. DOI: 10.4049/jimmunol.181.5.3099. [16] Van der Jeught K, Joe PT, Bialkowski L, et al. Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity[J]. Oncotarget, 2014,5(20):10100-10113. DOI: 10.18632/oncotarget.2463. [17] Marciscano AE, Haimovitz-Friedman A, Lee P, et al.Immunomodulatory effects of stereotactic body radiation therapy: preclinical insights and clinical opportunities[J]. Int J Radiat Oncol Biol Phys, 2021,110(1):35-52. DOI: 10.1016/j.ijrobp.2019.02.046. [18] Formenti SC, Rudqvist NP, Golden E, et al.Radiotherapy induces responses of lung cancer to CTLA-4 blockade[J]. Nat Med, 2018,24(12):1845-1851. DOI: 10.1038/s41591-018-0232-2. [19] Corrales L, McWhirter SM, Dubensky TW, et al. The host STING pathway at the interface of cancer and immunity[J]. J Clin Invest, 2016,126(7):2404-2411. DOI: 10.1172/JCI86892. [20] Liang H, Deng LF, Hou YZ, et al.Host STING-dependent MDSC mobilization drives extrinsic radiation resistance[J]. Nat Commun, 2017,8(1):1736. DOI: 10.1038/s41467-017-01566-5. [21] Nagarsheth N, Wicha MS, Zou WP.Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy[J]. Nat Rev Immunol, 2017,17(9):559-572. DOI: 10.1038/nri.2017.49. [22] Santagata S, Napolitano M, D'Alterio C, et al. Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer[J]. Oncotarget, 2017,8(44):77110-77120. DOI: 10.18632/oncotarget.20363. [23] Meiron M, Zohar Y, Anunu R, et al.CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells[J]. J Exp Med, 2008,205(11):2643-2655. DOI: 10.1084/jem.20080730. [24] Wang ZH, Tang Y, Tan YN, et al.Cancer-associated fibroblasts in radiotherapy: challenges and new opportunities[J]. Cell Commun Signal, 2019,17(1):47. DOI: 10.1186/s12964-019-0362-2. [25] Wennerberg E, Lhuillier C, Vanpouille-Box C, et al.Barriers to radiation-induced in situ tumor vaccination[J]. Front Immunol, 2017,8:229. DOI: 10.3389/fimmu.2017.00229. [26] Darragh LB, Oweida AJ, Karam SD.Overcoming resistance to combination radiation-immunotherapy: a focus on contributing pathways within the tumor micro- environment[J]. Front Immunol, 2018,9:3154. DOI: 10.3389/fimmu.2018.03154. [27] Barker HE, Paget JT, Khan AA, et al.The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence[J]. Nat Rev Cancer, 2015,15(7):409-425. DOI: 10.1038/nrc3958. [28] Postow MA, Callahan MK, Barker CA, et al.Immunologic correlates of the abscopal effect in a patient with melanoma[J]. N Engl J Med, 2012,366(10):925-931. DOI: 10.1056/NEJMoa1112824. [29] Stone HB, Peters LJ, Milas L.Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma[J]. J Natl Cancer Inst, 1979,63(5):1229-1235. [30] Spanos WC, Nowicki P, Lee DW, et al.Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer[J]. Arch Otolaryngol Head Neck Surg, 2009,135(11):1137-1146. DOI: 10.1001/archoto.2009.159. [31] Chera BS, Amdur RJ, Mendenhall W, et al.Beware of deintensification of radiation therapy in patients with p16-positive oropharynx cancer and rheumatological diseases[J]. Pract Radiat Oncol, 2017,7(4):e261-e262. DOI: 10.1016/j.prro.2016.12.004. [32] Lövey J, Polgár C.[Combination of radiation and immunotherapy in cancer treatment][J]. Magy Onkol, 2019,63(3):196-201. [33] Demaria S, Kawashima N, Yang AM, et al.Immune- mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer[J]. Clin Cancer Res, 2005,11(2 Pt 1):728-734. [34] Ricci MS, Zong WX.Chemotherapeutic approaches for targeting cell death pathways[J]. Oncologist, 2006,11(4):342-357. DOI: 10.1634/theoncologist.11-4-342. [35] Lauber K, Ernst A, Orth M, et al.Dying cell clearance and its impact on the outcome of tumor radiotherapy[J]. Front Oncol, 2012,2:116. DOI: 10.3389/fonc.2012.00116. [36] Dewan MZ, Galloway AE, Kawashima N, et al.Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody[J]. Clin Cancer Res, 2009,15(17):5379-5388. DOI: 10.1158/1078-0432.CCR-09-0265. [37] Vanpouille-Box C, Alard A, Aryankalayil MJ, et al.DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity[J]. Nat Commun, 2017,8:15618. DOI: 10.1038/ncomms15618. [38] Chandra RA, Wilhite TJ, Balboni TA, et al.A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab[J]. Oncoimmunology, 2015,4(11):e1046028. DOI: 10.1080/2162402X.2015.1046028. [39] Klug F, Prakash H, Huber PE, et al.Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy[J]. Cancer Cell, 2013,24(5):589-602. DOI: 10.1016/j.ccr.2013.09.014. [40] Prakash H, Klug F, Nadella V, et al.Low doses of gamma irradiation potentially modifies immunosuppressive tumor microenvironment by retuning tumor-associated macrophages: lesson from insulinoma[J]. Carcinogenesis, 2016,37(3):301-313. DOI: 10.1093/carcin/bgw007. [41] Reits EA, Hodge JW, Herberts CA, et al.Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy[J]. J Exp Med, 2006,203(5):1259-1271. DOI: 10.1084/jem.20052494. [42] Vanpouille-Box C, Formenti SC, Demaria S.TREX1 dictates the immune fate of irradiated cancer cells[J]. Oncoimmunology, 2017,6(9):e1339857. DOI: 10.1080/2162402X.2017.1339857. [43] Park HJ, Griffin RJ, Hui S, et al.Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS)[J]. Radiat Res, 2012,177(3):311-327. DOI: 10.1667/rr2773.1. [44] Hellevik T, Martinez-Zubiaurre I.Radiotherapy and the tumor stroma: the importance of dose and fractionation[J]. Front Oncol, 2014,4:1. DOI: 10.3389/fonc.2014.00001. [45] Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al.Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade[J]. Cancer Res, 2014,74(19):5458-5468. DOI: 10.1158/0008-5472.CAN-14-1258. [46] Wu CT, Chen WC, Chang YH, et al.The role of PD-L1 in the radiation response and clinical outcome for bladder cancer[J]. Sci Rep, 2016,6:19740. DOI: 10.1038/srep19740. [47] Young KH, Baird JR, Savage T, et al.Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy[J]. PLoS One, 2016,11(6):e0157164. DOI: 10.1371/journal.pone.0157164. [48] Shaverdian N, Lisberg AE, Bornazyan K, et al.Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial[J]. Lancet Oncol, 2017,18(7):895-903. DOI: 10.1016/S1470-2045(17)30380-7. [49] Frey B, Rubner Y, Wunderlich R, et al.Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation- implications for cancer therapies[J]. Curr Med Chem, 2012,19(12):1751-1764. DOI: 10.2174/092986712800099811. [50] Antonia SJ, Villegas A, Daniel D, et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer[J]. N Engl J Med, 2017,377(20):1919-1929. DOI: 10.1056/NEJMoa1709937. [51] Bernstein MB, Krishnan S, Hodge JW, et al.Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach?[J]. Nat Rev Clin Oncol, 2016,13(8):516-524. DOI: 10.1038/nrclinonc.2016.30. [52] Colaco RJ, Martin P, Kluger HM, et al.Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases?[J]. J Neurosurg, 2016,125(1):17-23. DOI: 10.3171/2015.6.JNS142763. [53] Kaidar-Person O, Zagar TM, Deal A, et al.The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy[J]. Anticancer Drugs, 2017,28(6):669-675. DOI: 10.1097/CAD.0000000000000497. [54] Fang P, Jiang W, Allen P, et al.Radiation necrosis with stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic melanoma[J]. J Neurooncol, 2017,133(3):595-602. DOI: 10.1007/s11060-017-2470-4. [55] Wrona A.Role of immunotherapy in stage III nonsmall cell lung cancer[J]. Curr Opin Oncol, 2019,31(1):18-23. DOI: 10.1097/CCO.0000000000000493. [56] Wilkins A, McDonald F, Harrington K, et al. Radiotherapy enhances responses of lung cancer to CTLA-4 blockade[J]. J Immunother Cancer, 2019,7(1):64. DOI: 10.1186/s40425-019-0542-z. [57] Ukleja J, Kusaka E, Miyamoto DT.Immunotherapy combined with radiation therapy for genitourinary malignancies[J]. Front Oncol, 2021,11:663852. DOI: 10.3389/fonc.2021.663852. [58] Evans JD, Morris LK, Zhang H, et al.Prospective immunophenotyping of CD8(+) T cells and associated clinical outcomes of patients with oligometastatic prostate cancer treated with metastasis-directed SBRT[J]. Int J Radiat Oncol Biol Phys, 2019,103(1):229-240. DOI: 10.1016/j.ijrobp.2018.09.001. [59] Sun R, Limkin EJ, Vakalopoulou M, 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[J]. Lancet Oncol, 2018,19(9):1180-1191. DOI: 10.1016/S1470-2045(18)30413-3. [60] Krieg C, Nowicka M, Guglietta S, et al.High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy[J]. Nat Med, 2018,24(2):144-153. DOI: 10.1038/nm.4466.