Combining Immunotherapy and Radiotherapy for Cancer Treatment: Current Challenges and Future Directions

Yifan Wang, Weiye Deng, Nan Li, Shinya Neri, Amrish Sharma, Wen Jiang, Steven H Lin, Yifan Wang, Weiye Deng, Nan Li, Shinya Neri, Amrish Sharma, Wen Jiang, Steven H Lin

Abstract

Since the approval of anti-CTLA4 therapy (ipilimumab) for late-stage melanoma in 2011, the development of anticancer immunotherapy agents has thrived. The success of many immune-checkpoint inhibitors has drastically changed the landscape of cancer treatment. For some types of cancer, monotherapy for targeting immune checkpoint pathways has proven more effective than traditional therapies, and combining immunotherapy with current treatment strategies may yield even better outcomes. Numerous preclinical studies have suggested that combining immunotherapy with radiotherapy could be a promising strategy for synergistic enhancement of treatment efficacy. Radiation delivered to the tumor site affects both tumor cells and surrounding stromal cells. Radiation-induced cancer cell damage exposes tumor-specific antigens that make them visible to immune surveillance and promotes the priming and activation of cytotoxic T cells. Radiation-induced modulation of the tumor microenvironment may also facilitate the recruitment and infiltration of immune cells. This unique relationship is the rationale for combining radiation with immune checkpoint blockade. Enhanced tumor recognition and immune cell targeting with checkpoint blockade may unleash the immune system to eliminate the cancer cells. However, challenges remain to be addressed to maximize the efficacy of this promising combination. Here we summarize the mechanisms of radiation and immune system interaction, and we discuss current challenges in radiation and immune checkpoint blockade therapy and possible future approaches to boost this combination.

Keywords: biomarkers; cancer treatment; immune checkpoints; immunotherapy; radiotherapy.

Figures

Figure 1
Figure 1
Current challenges in combining radiotherapy with immunotherapy. (A) Optimization of treatment timing: using immunotherapy concurrently, sequentially, or as neoadjuvant therapy with radiotherapy. (B) Optimization of radiation dosing: conventional fractionation or hypofractionation. (C) Reduction of the radiation-induced toxicity of circulating and tumor-infiltrated lymphocytes. (D) Selection of immunoradiation therapy or standard therapy for patients based on predictive biomarkers.

References

    1. Ahn J., Xia T., Konno H., Konno K., Ruiz P., Barber G. N. (2014). Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun. 5:5166. 10.1038/ncomms6166
    1. Alomari A. K., Cohen J., Vortmeyer A. O., Chiang A., Gettinger S., Goldberg S., et al. . (2016). Possible interaction of anti-PD-1 therapy with the effects of radiosurgery on brain metastases. Cancer Immunol. Res. 4, 481–487. 10.1158/2326-6066.CIR-15-0238
    1. Alotaibi M., Sharma K., Saleh T., Povirk L. F., Hendrickson E. A., Gewirtz D. A. (2016). Radiosensitization by PARP inhibition in DNA repair proficient and deficient tumor cells: proliferative recovery in senescent cells. Radiat. Res. 185, 229–245. 10.1667/RR14202.1
    1. Alsaab H. O., Sau S., Alzhrani R., Tatiparti K., Bhise K., Kashaw S. K., et al. . (2017). PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front. Pharmacol. 8:561. 10.3389/fphar.2017.00561
    1. Antonia S. J., Villegas A., Daniel D., Vicente D., Murakami S., Hui R., et al. . (2017). Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929. 10.1056/NEJMoa1709937
    1. Aryankalayil M. J., Makinde A. Y., Gameiro S. R., Hodge J. W., Rivera-Solis P. P., Palayoor S. T., et al. . (2014). Defining molecular signature of pro-immunogenic radiotherapy targets in human prostate cancer cells. Radiat. Res. 182, 139–148. 10.1667/RR13731.1
    1. Baird J. R., Friedman D., Cottam B., Dubensky T. W., Jr., Kanne D. B., Bambina S., et al. . (2016). Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors. Cancer Res. 76, 50–61. 10.1158/0008-5472.CAN-14-3619
    1. Balachandran V. P., Łuksza M., Zhao J. N., Makarov V., Moral J. A., Remark R., et al. . (2017). Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516. 10.1038/nature24462
    1. Barker H. E., Paget J. T., Khan A. A., Harrington K. J. (2015). The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425. 10.1038/nrc3958
    1. Borghaei H., Paz-Ares L., Horn L., Spigel D. R., Steins M., Ready N. E., et al. . (2015). Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639. 10.1056/NEJMoa1507643
    1. Camphausen K., Moses M. A., Ménard C., Sproull M., Beecken W. D., Folkman J., et al. . (2003). Radiation abscopal antitumor effect is mediated through p53. Cancer Res. 63, 1990–1993.
    1. Chalmers Z. R., Connelly C. F., Fabrizio D., Gay L., Ali S. M., Ennis R., et al. . (2017). Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9:34. 10.1186/s13073-017-0424-2
    1. Chen A. Y., Phan C., Chang Y. C., Shih S. J. (2004). Targeted radiosensitization with DNA topoisomerase I drugs. Discov. Med. 4, 208–212.
    1. Cho O., Oh Y. T., Chun M., Noh O. K., Hoe J. S., Kim H. (2016). Minimum absolute lymphocyte count during radiotherapy as a new prognostic factor for nasopharyngeal cancer. Head Neck 38, E1061–E1067. 10.1002/hed.24158
    1. Chowell D., Morris L. G. T., Grigg C. M., Weber J. K., Samstein R. M., Makarov V., et al. . (2017). Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359, 582–587. 10.1126/science.aao4572
    1. Corrales L., Glickman L. H., McWhirter S. M., Kanne D. B., Sivick K. E., Katibah G. E., et al. . (2015). Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030. 10.1016/j.celrep.2015.04.031
    1. Corrales L., McWhirter S. M., Dubensky T. W., Gajewski T. F. (2016). The host STING pathway at the interface of cancer and immunity. J. Clin. Invest. 126, 2404–2411. 10.1172/JCI86892
    1. Cortez M. A., Ivan C., Valdecanas D., Wang X., Peltier H. J., Ye Y., et al. . (2016). PDL1 regulation by p53 via miR-34. J. Natl. Cancer Inst. 108:djv303. 10.1093/jnci/djv303
    1. Daud A. I., Loo K., Pauli M. L., Sanchez-Rodriguez R., Sandoval P. M., Taravati K., et al. . (2016). Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J. Clin. Invest. 126, 3447–3452. 10.1172/JCI87324
    1. Davuluri R., Jiang W., Fang P., Xu C., Komaki R., Gomez D. R., et al. . (2017). Lymphocyte nadir and esophageal cancer survival outcomes after chemoradiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 99, 128–135. 10.1016/j.ijrobp.2017.05.037
    1. Demaria S., Ng B., Devitt M. L., Babb J. S., Kawashima N., Liebes L., et al. . (2004). Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58, 862–870. 10.1016/j.ijrobp.2003.09.012
    1. Deng L., Liang H., Burnette B., Beckett M., Darga T., Weichselbaum R. R., et al. . (2014a). Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695. 10.1172/JCI67313
    1. Deng L., Liang H., Xu M., Yang X., Burnette B., Arina A., et al. . (2014b). STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852. 10.1016/j.immuni.2014.10.019
    1. Deschavanne P. J., Fertil B. (1996). A review of human cell radiosensitivity in vitro. Int. J. Radiat. Oncol. Biol. Phys. 34, 251–266. 10.1016/0360-3016(95)02029-2
    1. Dewan M. Z., Galloway A. E., Kawashima N., Dewyngaert J. K., Babb J. S., Formenti S. C., et al. (2009). Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388. 10.1158/1078-0432.CCR-09-0265
    1. Diem S., Kasenda B., Spain L., Martin-Liberal J., Marconcini R., Gore M., et al. . (2016). Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br. J. Cancer 114, 256–261. 10.1038/bjc.2015.467
    1. Dovedi S. J., Adlard A. L., Lipowska-Bhalla G., McKenna C., Jones S., Cheadle E. J., et al. . (2014). Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 74, 5458–5468. 10.1158/0008-5472.CAN-14-1258
    1. Essink A., Korse T., van den Heuvel M. (2016). 157P: serum tumor markers and the response to immunotherapy in advanced non-small cell lung carcinoma. J. Thorac. Oncol. 11:S126. 10.1016/S1556-0864(16)30267-2
    1. Feng F. Y., Speers C., Liu M., Jackson W. C., Moon D., Rinkinen J., et al. . (2014). Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer. Breast Cancer Res. Treat. 147, 81–94. 10.1007/s10549-014-3085-5
    1. Flynn J. P., O'Hara M. H., Gandhi S. J. (2017). Preclinical rationale for combining radiation therapy and immunotherapy beyond checkpoint inhibitors (i.e., CART). Transl. Lung Cancer Res. 6, 159–168. 10.21037/tlcr.2017.03.07
    1. Frey B., Rückert M., Deloch L., Rühle P. F., Derer A., Fietkau R., et al. . (2017). Immunomodulation by ionizing radiation-impact for design of radio-immunotherapies and for treatment of inflammatory diseases. Immunol. Rev. 280, 231–248. 10.1111/imr.12572
    1. Germano G., Lamba S., Rospo G., Barault L., Magrì A., Maione F., et al. . (2017). Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120. 10.1038/nature24673
    1. Girdhani S., Bhosle S. M., Thulsidas S. A., Kumar A., Mishra K. P. (2005). Potential of radiosensitizing agents in cancer chemo-radiotherapy. J. Cancer Res. Ther. 1, 129–131. 10.4103/0973-1482.19585
    1. Golden E. B., Pellicciotta I., Demaria S., Barcellos-Hoff M. H., Formenti S. C. (2012). The convergence of radiation and immunogenic cell death signaling pathways. Front. Oncol. 2:88. 10.3389/fonc.2012.00088
    1. Gopalakrishnan V., Spencer C. N., Nezi L., Reuben A., Andrews M. C., Karpinets T. V., et al. . (2017). Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103. 10.1126/science.aan4236
    1. Hanahan D., Weinberg R. A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674. 10.1016/j.cell.2011.02.013
    1. Haymaker C. L., Kim D., Uemura M., Vence L. M., Phillip A., McQuail N., et al. . (2017). Metastatic melanoma patient had a complete response with clonal expansion after whole brain radiation and PD-1 blockade. Cancer Immunol. Res. 5, 100–105. 10.1158/2326-6066.CIR-16-0223
    1. Herbst R. S., Soria J. C., Kowanetz M., Fine G. D., Hamid O., Gordon M. S., et al. . (2014). Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567. 10.1038/nature14011
    1. Hryniewicz A., Boasso A., Edghill-Smith Y., Vaccari M., Fuchs D., Venzon D., et al. . (2006). CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood 108, 3834–3842. 10.1182/blood-2006-04-010637
    1. Ishikawa H., Ma Z., Barber G. N. (2009). STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792. 10.1038/nature08476
    1. Jiang W., Chan C. K., Weissman I. L., Kim B. Y. S., Hahn S. M. (2016). Immune priming of the tumor microenvironment by radiation. Trends Cancer 2, 638–645. 10.1016/j.trecan.2016.09.007
    1. Jiao S., Xia W., Yamaguchi H., Wei Y., Chen M. K., Hsu J. M., et al. . (2017). PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin. Cancer Res. 23, 3711–3720. 10.1158/1078-0432.CCR-16-3215
    1. Kalbasi A., June C. H., Haas N., Vapiwala N. (2013). Radiation and immunotherapy: a synergistic combination. J. Clin. Invest. 123, 2756–2763. 10.1172/JCI69219
    1. Kang J., Demaria S., Formenti S. (2016). Current clinical trials testing the combination of immunotherapy with radiotherapy. J. Immunother. Cancer 4:51. 10.1186/s40425-016-0156-7
    1. Khagi Y., Goodman A. M., Daniels G. A., Patel S. P., Sacco A. G., Randall J. M., et al. . (2017). Hypermutated circulating tumor DNA: correlation with response to checkpoint inhibitor-based immunotherapy. Clin. Cancer Res. 23, 5729–5736. 10.1158/1078-0432.CCR-17-1439
    1. Klopp A. H., Spaeth E. L., Dembinski J. L., Woodward W. A., Munshi A., Meyn R. E., et al. . (2007). Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res. 67, 11687–11695. 10.1158/0008-5472.CAN-07-1406
    1. Ku G. Y., Yuan J., Page D. B., Schroeder S. E., Panageas K. S., Carvajal R. D., et al. . (2010). Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting lymphocyte count after 2 doses correlates with survival. Cancer 116, 1767–1775. 10.1002/cncr.24951
    1. Kumar S. S., Higgins K. A., McGarry R. C. (2017). Emerging therapies for stage III non-small cell lung cancer: stereotactic body radiation therapy and immunotherapy. Front. Oncol. 7:197. 10.3389/fonc.2017.00197
    1. Kumar V., Chaudhary N., Garg M., Floudas C. S., Soni P., Chandra A. B. (2017). Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front. Pharmacol. 8:49 10.3389/fphar.2017.00049
    1. Lawrence T. S., Blackstock A. W., McGinn C. (2003). The mechanism of action of radiosensitization of conventional chemotherapeutic agents. Semin. Radiat. Oncol. 13, 13–21. 10.1053/srao.2003.50002
    1. Le D. T., Durham J. N., Smith K. N., Wang H., Bartlett B. R., Aulakh L. K., et al. . (2017). Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413. 10.1126/science.aan6733
    1. Le D. T., Uram J. N., Wang H., Bartlett B. R., Kemberling H., Eyring A. D., et al. . (2015). PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520. 10.1056/NEJMoa1500596
    1. Lee Y., Auh S. L., Wang Y., Burnette B., Wang Y., Meng Y., et al. . (2009). Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114, 589–595. 10.1182/blood-2009-02-206870
    1. Lemos H., Mohamed E., Huang L., Ou R., Pacholczyk G., Arbab A. S., et al. . (2016). STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 76, 2076–2081. 10.1158/0008-5472.CAN-15-1456
    1. Li X. D., Wu J., Gao D. X., Wang H., Sun L., Chen Z. J. (2013). Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390–1394. 10.1126/science.1244040
    1. Liang H., Deng L., Hou Y., Meng X., Huang X., Rao E., et al. . (2017). Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 8:1736. 10.1038/s41467-017-01566-5
    1. Liikanen I., Koski A., Merisalo-Soikkeli M., Hemminki O., Oksanen M., Kairemo K., et al. . (2015). Serum HMGB1 is a predictive and prognostic biomarker for oncolytic immunotherapy. Oncoimmunology 4:e989771. 10.4161/2162402X.2014.989771
    1. Liu J., Liao S., Diop-Frimpong B., Chen W., Goel S., Naxerova K., et al. . (2012). TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc. Natl. Acad. Sci. U.S.A. 109, 16618–16623. 10.1073/pnas.1117610109
    1. Lugade A. A., Moran J. P., Gerber S. A., Rose R. C., Frelinger J. G., Lord E. M. (2005). Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol. 174, 7516–7523. 10.4049/jimmunol.174.12.7516
    1. Łuksza M., Riaz N., Makarov V., Balachandran V. P., Hellmann M. D., Solovyov A., et al. . (2017). A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520. 10.1038/nature24473
    1. Marciscano A. E., Nirschl T. R., Francica B. J., Ghasemzadeh A., Theodros D., Velarde E., et al. (2016). Does prophylactic nodal irradiation inhibit potential synergy between radiation therapy and immunotherapy? Int. J. Radiat. Oncol. Biol. Phys. 96:S88 10.1016/j.ijrobp.2016.06.222
    1. Marincola F. M., Jaffee E. M., Hicklin D. J., Ferrone S. (2000). Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv. Immunol. 74, 181–273. 10.1016/S0065-2776(08)60911-6
    1. Martin A. M., Cagney D. N., Catalano P. J., Alexander B. M., Redig A. J., Schoenfeld J. D., et al. . (2018). Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation. JAMA Oncol. [Epub ahead of print]. 10.1001/jamaoncol.2017.3993
    1. Milas L., Fan Z., Andratschke N. H., Ang K. K. (2004). Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int. J. Rad. Oncol. Biol. Phys. 58, 966–971. 10.1016/j.ijrobp.2003.08.035
    1. Nagasaka M., Zaki M., Kim H., Raza S. N., Yoo G., Lin H. S., et al. . (2016). PD1/PD-L1 inhibition as a potential radiosensitizer in head and neck squamous cell carcinoma: a case report. J. Immunother. Cancer 4:83. 10.1186/s40425-016-0187-0
    1. Nishino M., Ramaiya N. H., Hatabu H., Hodi F. S. (2017). Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol. 14, 655–668. 10.1038/nrclinonc.2017.88
    1. Obeid M., Tesniere A., Ghiringhelli F., Fimia G. M., Apetoh L., Perfettini J. L., et al. . (2007). Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61. 10.1038/nm1523
    1. Oshima Y., Tanimoto T., Yuji K., Tojo A. (2018). EGFR-TKI-Associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol. [Epub ahead of print]. 10.1001/jamaoncol.2017.4526
    1. Perrin P. J., Maldonado J. H., Davis T. A., June C. H., Racke M. K. (1996). CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis. J. Immunol. 157, 1333–1336.
    1. Qian J. M., Yu J. B., Kluger H. M., Chiang V. L. (2016). Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 122, 3051–3058. 10.1002/cncr.30138
    1. Reits E. A., Hodge J. W., Herberts C. A., Groothuis T. A., Chakraborty M., Wansley E. K., et al. . (2006). Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271. 10.1084/jem.20052494
    1. Remon J., Chaput N., Planchard D. (2016). Predictive biomarkers for programmed death-1/programmed death ligand immune checkpoint inhibitors in nonsmall cell lung cancer. Curr. Opin. Oncol. 28, 122–129. 10.1097/CCO.0000000000000263
    1. Rizvi N. A., Mazières J., Planchard D., Stinchcombe T. E., Dy G. K., Antonia S. J., et al. . (2015). Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265. 10.1016/S1470-2045(15)70054-9
    1. Samstein R., Rimner A., Barker C. A., Yamada Y. (2017). Combined immune checkpoint blockade and radiation therapy: timing and dose fractionation associated with greatest survival duration among over 750 treated patients. Int. J. Radiat. Oncol. Biol. Phys. 99(2Suppl.), S129–S130. 10.1016/j.ijrobp.2017.06.303
    1. Schoenfeld J., Jinushi M., Nakazaki Y., Wiener D., Park J., Soiffer R., et al. . (2010). Active immunotherapy induces antibody responses that target tumor angiogenesis. Cancer Res. 70, 10150–10160. 10.1158/0008-5472.CAN-10-1852
    1. Schoenhals J. E., Seyedin S. N., Tang C., Cortez M. A., Niknam S., Tsouko E., et al. . (2016). Preclinical rationale and clinical considerations for radiotherapy plus immunotherapy: going beyond local control. Cancer J. 22, 130–137. 10.1097/PPO.0000000000000181
    1. Schumacher T. N., Schreiber R. D. (2015). Neoantigens in cancer immunotherapy. Science 348, 69–74. 10.1126/science.aaa4971
    1. Sharma S., DeOliveira R. B., Kalantari P., Parroche P., Goutagny N., Jiang Z., et al. . (2011). Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. Immunity 35, 194–207. 10.1016/j.immuni.2011.05.016
    1. Shaverdian N., Lisberg A. E., Bornazyan K., Veruttipong D., Goldman J. W., Formenti S. C., et al. . (2017). 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. Lancet Oncol. 18, 895–903. 10.1016/S1470-2045(17)30380-7
    1. Shi F., Wang X., Teng F., Kong L., Yu J. (2017). Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy. Cancer Biol. Ther. 18, 137–141. 10.1080/15384047.2016.1276133
    1. Shiraishi Y., Fang P., Xu C., Song J., Krishnan S., Koay E. J., et al. . (2017). Severe lymphopenia during neoadjuvant chemoradiation for esophageal cancer: a propensity matched analysis of the relative risk of proton versus photon-based radiation therapy. Radiother. Oncol. [Epub ahead of print]. 10.1016/j.radonc.2017.11.028
    1. Shukuya T., Carbone D. P. (2016). Predictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in lung cancer. J. Thorac. Oncol. 11, 976–988. 10.1016/j.jtho.2016.02.015
    1. Son C. H., Fleming G. F., Moroney J. W. (2017). Potential role of radiation therapy in augmenting the activity of immunotherapy for gynecologic cancers. Cancer Manag. Res. 9, 553–563. 10.2147/CMAR.S116683
    1. Sun L., Wu J., Du F., Chen X., Chen Z. J. (2013). Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791. 10.1126/science.1232458
    1. Tanaka Y., Chen Z. J. (2012). STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal 5:ra20. 10.1126/scisignal.2002521
    1. Tang C., Jiang W., Yap T. A. (2018). Efficacy and toxic effects of cancer immunotherapy combinations-a double-edged sword. JAMA Oncol. [Epub ahead of print]. 10.1001/jamaoncol.2017.4606
    1. Tang C., Liao Z., Gomez D., Levy L., Zhuang Y., Gebremichael R. A., et al. . (2014). Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int. J. Radiat. Oncol. Biol. Phys. 89, 1084–1091. 10.1016/j.ijrobp.2014.04.025
    1. Topalian S. L., Hodi F. S., Brahmer J. R., Gettinger S. N., Smith D. C., McDermott D. F., et al. . (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Eng. J. Med. 366, 2443–2454. 10.1056/NEJMoa1200690
    1. Torphy R. J., Schulick R. D., Zhu Y. (2017). Newly emerging immune checkpoints: promises for future cancer therapy. Int. J. Mol. Sci. 18:E2642. 10.3390/ijms18122642
    1. Trapani J. A. (2005). The dual adverse effects of TGF-beta secretion on tumor progression. Cancer Cell 8, 349–350. 10.1016/j.ccr.2005.10.018
    1. Twyman-Saint Victor C., Rech A. J., Maity A., Rengan R., Pauken K. E., Stelekati E., et al. . (2015). Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377. 10.1038/nature14292
    1. Vanpouille-Box C., Alard A., Aryankalayil M. J., Sarfraz Y., Diamond J. M., Schneider R. J., et al. . (2017). DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8:15618. 10.1038/ncomms15618
    1. Vanpouille-Box C., Diamond J. M., Pilones K. A., Zavadil J., Babb J. S., Formenti S. C., et al. (2015). TGF beta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 75, 2232–2242. 10.1158/0008-5472.CAN-14-3511
    1. Vermeer D. W., Spanos W. C., Vermeer P. D., Bruns A. M., Lee K. M., Lee J. H. (2013). Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer. Int. J. Cancer 133, 120–129. 10.1002/ijc.28015
    1. Vétizou M., Pitt J. M., Daillère R., Lepage P., Waldschmitt N., Flament C., et al. . (2015). Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084. 10.1126/science.aad1329
    1. Wang Y., Liu H., Diao L., Potter A., Zhang J., Qiao Y., et al. . (2016). Hsp90 inhibitor ganetespib sensitizes non-small cell lung cancer to radiation but has variable effects with chemoradiation. Clin. Cancer Res. 22, 5876–5886. 10.1158/1078-0432.CCR-15-2190
    1. Watson R. O., Manzanillo P. S., Cox J. S. (2012). Extracellular, M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803–815. 10.1016/j.cell.2012.06.040
    1. Wei S. C., Levine J. H., Cogdill A. P., Zhao Y., Anang N. A. S., Andrews M. C., et al. . (2017). Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120.e17–1133.e17. 10.1016/j.cell.2017.07.024
    1. Weichselbaum R. R., Liang H., Deng L., Fu Y. X. (2017). Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379. 10.1038/nrclinonc.2016.211
    1. Wrzesinski S. H., Wan Y. Y., Flavell R. A. (2007). Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin. Cancer Res. 13(18 Pt 1), 5262–5270. 10.1158/1078-0432.CCR-07-1157
    1. Xia T., Konno H., Ahn J., Barber G. N. (2016a). Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 14, 282–297. 10.1016/j.celrep.2015.12.029
    1. Xia T., Konno H., Barber G. N. (2016b). Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. Cancer Res. 76, 6747–6759. 10.1158/0008-5472.CAN-16-1404
    1. Yang L., Pang Y., Moses H. L. (2010). TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31, 220–227. 10.1016/j.it.2010.04.002
    1. Ye J. C., Formenti S. C. (2017). Integration of radiation and immunotherapy in breast cancer - treatment implications. Breast 38, 66–74. 10.1016/j.breast.2017.12.005
    1. Yoshimoto Y., Oike T., Okonogi N., Suzuki Y., Ando K., Sato H., et al. . (2015). Carbon-ion beams induce production of an immune mediator protein, high mobility group box 1, at levels comparable with X-ray irradiation. J. Radiat. Res. 56, 509–514. 10.1093/jrr/rrv007
    1. Young K. H., Baird J. R., Savage T., Cottam B., Friedman D., Bambina S., et al. . (2016). Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS ONE 11:e0157164. 10.1371/journal.pone.0157164
    1. Yuan H., Jiang W., von Roemeling C. A., Qie Y., Liu X., Chen Y., et al. . (2017). Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nat. Nanotechnol. 12, 763–769. 10.1038/nnano.2017.69

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