Abstract: Radiotherapy (RT) is used as primary treatment for numerous cancers. Although it is usually described as an immunosuppressive modality,there are new preclinical evidences suggesting that RT could have also generated substantial changes in the tumor microenvironment,including triggering an inflammatory process. Some studies established the proof of concept that combining RT with strategies modifying immunology could enhance antitumor effects.
[1] Golden E B,Apetoh L.Radiotherapy and Immunogenic Cell Death[J].Sem Radiat Oncol,2015,25(1):11-17.DOI:10.1016/j.semradonc.2014.07.005. [2] Lee Y,Auh SL,WangY,et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells:Changing strategies for cancer treatment[J]. Blood, 2009, 114(3):589-595.DOI:10.1182/blood-2009-02-206870. [3] Law AW,Mole RH.Direct and abscopal effects of x-radiation on the thymus of the weanling rat[J].Int J Radiat Biol,1961,3(2):233-248. [4] Stamell EF,Wolchok JD,Gnjatic S,et al. The abscopal effect associated with a systemic anti-melanoma immune response[J].Int J Radiat Oncol Biol Phys. 2013,85(2):293-295.DOI:10.1016/j.ijrobp.2012.03.017 [5] 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. [6] Hiniker SM,Chen DS,Reddy S,et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy[J].Transl Oncol,2012,5(6):404-407. [7] Gameiro S R,Ardiani A,Kwilas A,et al. Radiation-induced survival responses promote immunogenic modulation to enhance immunotherapy in combinatorial regimens.[J].Oncoimmunology,2014,3(5):371-379.DOI:10.4161/onci.28643 [8] Kepp O,Senovilla L,Vitale I,et al. Consensus guidelines for the detection of immunogenic cell death[J].Oncoimmunology,2014,3(9):12472-124508.DOI:10.4161/21624011. [9] Zhang B,Bowerman NA,Salama JK,et al. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells[J].J Exp Med,2007,204(1):49-55.DOI:10.1084/jem.20062056. [10] Demaria S,Coleman CN,Formenti SC.Radiotherapy:changing the game in immunotherapy[J].Trend Cancer,2016,2(6):286-294.DOI:10.1016/j.trecan.2016.05.002. [11] Apetoh L,Ghiringhelli F,Tesniere A,et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy[J].Nat Med,2007,13(9):1050-1059.DOI:10.1038/nm1622. [12] Lugade AA,Sorensen EW,Gerber SA,et al. Radiation induced IFN-gamma production within the tumor microenvironment influences antitumor immunity[J].J Immunol,2008,180(5):3132-3134. [13] Parker JJ,Jones JC,Strober S,et al. Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line[J].Clin Immunol,2013,148(1):44-55.DOI:10.1016/j.clim.2013.03.008. [14] Wattenberg MM,Kwilas AR,Gameiro SR,et al. Expanding the use of monoclonal antibody therapy of cancer by using ionising radiation to upregulate antibody targets[J].Br J Cancer,2014,110(6):1472-1480.DOI:10.1038/bjc.2014.79. [15] Wan S,Pestka S,Jubin RG,et al. Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells[J/OL].PLoS One,2012,7(3):e32542. [16] Reits EA,Hodge JW,Herberts CA,et al. Radiation modulates the peptide repertoire,enhances MHC class I expression,and induces successful anti-tumor immunotherapy[J].J Exp Med,2006,203(5):1259-1271. [17] Gameiro SR,Jammeh ML,Wattenberg MM,et al. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure,resulting in enhanced T-cell killing[J].Oncotarget,2014,5(2):403-416.DOI:10.18632/oncotarget.1719. [18] Anu Sharma,Beata Bode,Roland H.et al.γ-radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo[J].PLoS One,2011,6(11):e28217.DOI:10.1371/journal.pone.0028217. [19] Barker CA,Postow MA.Combinations of radiation therapy and immunotherapy for melanoma:a review of clinical outcomes[J].Int J Radiat Oncol Biol Phys,2014,88(5):986-997.DOI:10.1016/j.ijrobp.2013.08.035. [20] Matsumura S,Demaria S.Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation[J].Radiat Res,2010,173(4):418-425.DOI:10.1016/j.ijrobp.2013.08.035. [21] 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. [22] 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. [23] Demaria S,Golden EB,Formenti SC.Role of local radiation therapy in cancer immunotherapy[J].Jama Oncol,2015,1(9):1325-1332.DOI:10.1001/jamaoncol.2015.2756. [24] Deng L,Liang H,Burnette B,et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J].J Clin Investigat,2014,124(2):687-695.DOI:10.1172/JCI67313. [25] Zeng J,See AP,Phallen J,et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas[J].Int J Radiat Oncol Biol Phys,2013,86(2):343-349.DOI:10.1016/j.ijrobp.2012.12.025. [26] Deng L,Liang H,Burnette B,et al. Irradiation and anti-PD-L1 treatment synergistically promote anti-tumor immunity in mice[J].J Clin Invest,2014,124(2):687-695.DOI:10.1172/JCI67313. [27] Verbrugge I,Hagekyriakou J,Sharp LL,et al. Radio-therapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies[J].Cancer Res,2012,72(13):3163-3174.DOI:10.4049/jimmunol.1202612. [28] Liang H,Deng L,Chmura S,et al. Radiation-induced equilibrium is a balance between tumor cell proliferation and T cell-mediated killing[J].J Immunol,2013,190(11):5874-5881.DOI:10.4049/jimmunol.1202612. [29] Pilones KA,Vanpouille-Box C,Demaria S.Combination of radiotherapy and immune checkpoint inhibitors[J].Sem Radiat Oncol,2015,25(1):28-33.DOI:10.1016/j.semradonc.2014.07.004. [30] Darby S,McGale P, Correa C,et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancerdeath:meta-analysis of individual patient data for 10,801 women in 17 randomised trials[J].Lancet,2011,378(9804):1707-1716.DOI:10.1016/S0140-6736(11)61629-2. [31] Younes E,Haas GP,Dezso B,et al. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma[J].Cell Immunol,1995,165(2):243-251. [32] Chakraborty M,Abrams SI,Coleman CN,et al. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing[J].Cancer Res,2004,64(12):4328-4337. [33] Draghiciu O,Walczak M,Hoogeboom BN,et al. Therapeutic immunization and local low-dose tumor irradiation,a reinforcing combination[J].Int J Cancer,2014,134(4):859-872.DOI:10.1002/ijc.28418. [34] Formenti SC,Demaria S.Combining radiotherapy and cancer immunotherapy:a paradigm shift[J].J Natl Cancer Inst,2013,105(4):256-265.DOI:10.1093/jnci/djs629. [35] Schaue D,Ratikan JA,Iwamoto KS,et al. Maximizing tumor immunity with fractionated radiation[J].Int J Radiat Oncol Biol Phys,2012,83(4):1306-1310.DOI:10.1016/j.ijrobp.2011.09.049. [36] Lugade AA,Moran JP,Gerber SA,et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor[J].J Immunol,2005,174(12):7516-7523. [37] Gulley JL,Arlen PM,Bastian A,et al. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer[J].Clin Cancer Res,2005,11(9):3353-3362. [38] Golden EB,Chhabra A,Chachoua A,et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours:a proof-of-principle trial[J].Lancet Oncol,2015,16(7):795-803.DOI:10.1016/S1470-2045(15)00054-6. [39] Finkelstein SE,Iclozan C,Bui MM,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[J].Int J Radiat Oncol Biol Phys,2012,82(2):924-932.DOI:10.1016/j.ijrobp.2010.12.068 [40] Hasumi K,Aoki Y,Wantanabe R,et al. Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy[J].Oncoimmunology,2013,2(10):e26381.DOI:10.4161/onci.26381. [41] Brody JD,Ai WZ,Czerwinski DK,et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression:a phase Ⅰ/Ⅱ study[J].J Clin Oncol,2010,28(28):4324-4332.DOI:10.1200/JCO.2010.28.9793. [42] Kim YH,Gratzinger D,Harrison C,et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation:a Phase Ⅰ/Ⅱ study[J].Blood,2012,119(2):355-363.DOI:10.1182/blood-2011-05-355222. [43] Seung SK,Curti BD,Crittenden M,et al. Phase I study of stereotactic body radiotherapy and interleukin-2-tumor and immunological responses[J].Sci Transl Med,2012,4(137):137-174.DOI:10.1126/scitranslmed.3003649. [44] Wolchok JD,Kluger H,Callahan MK,et al. Nivolumab plus ipilimumab in advanced melanoma[J].N Engl J Med,2013,369(2):122-133.DOI:10.1056/NEJMoa1302369. [45] Golden EB,Demaria S,Schiff PB,et al,An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer[J].Cancer Immunol Res,2013,1(6):365-372.DOI:10.1158/2326-6066.CIR-13-0115. [46] Golden EB,Chachoua A,Fenton-Kerimian MB,et al. Abscopal responses in metastatic non-small cell lung cancer (NSCLC) Patients treated on a phase 2 study of combined radiation therapy and ipilimumab:evidence for the in situ vaccination hypothesis of radiation[J].Int J Radiat Oncol Biol Phys,2015,93(3):S66-S67. [47] Slovin SF,Higano CS,Hamid O,et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer:results from an open-label,multicenter phase Ⅰ/Ⅱ study[J].Ann Oncol,2013,24(7):1813-1821.DOI:10.1093/annonc/mdt107. [48] Seyedin SN,Schoenhals JE,Lee DA,et al. Strategies for combining immunotherapy with radiation for anticancer therapy.[J].Immunotherapy,2015,7(9):967-980.DOI:10.2217/imt.15.65. [49] Silk AW,Bassetti MF,West BT,et al. Ipilimumab and radiation therapy for melanoma brain metastases[J].Cancer Med,2013,2(6):899-906.DOI:10.1002/cam4.140.