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Review

Effect of radiotherapy on T cell and PD-1 / PD-L1 blocking therapy in tumor microenvironment

, &
Pages 1555-1567 | Received 04 Aug 2020, Accepted 15 Oct 2020, Published online: 11 Jan 2021

References

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.21492.
  • Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, Znaor A, Bray F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144:1941–53.
  • Muroyama Y, Nirschl TR, Kochel CM, Lopez-Bujanda Z, Theodros D, Mao W, Carrera-Haro MA, Ghasemzadeh A, Marciscano AE, Velarde E, et al. Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol Res. 2017;5(11):992–1004. doi:10.1158/2326-6066.CIR-17-0040.
  • Darragh LB, Oweida AJ, Karam SD. Overcoming resistance to combination radiation-immunotherapy: a focus on contributing pathways within the tumor microenvironment. Front Immunol. 2018;9:3154. doi:10.3389/fimmu.2018.03154.
  • Jaffray DA. Image-guided radiotherapy: from current concept to future perspectives. Nat Rev Clin Oncol. 2012;9(12):688–99. doi:10.1038/nrclinonc.2012.194.
  • Janssen LME, Ramsay EE, Logsdon CD, Overwijk WW. The immune system in cancer metastasis: friend or foe? J Immunother Cancer. 2017;5:79. doi:10.1186/s40425-017-0283-9.
  • Gato-Canas M, Arasanz H, Blanco-Luquin I, Glaria E, Arteta-Sanchez V, Kochan G, Escors D. Novel immunotherapies for the treatment of melanoma. Immunotherapy. 2016;8:613–32. doi:10.2217/imt-2015-0024.
  • Chen G. Current situation and progress of immunotherapy for colorectal cancer. J Precis Med. 2019;34:1–5.
  • Bockel S, Durand B, Deutsch E. Combining radiation therapy and cancer immune therapies: from preclinical findings to clinical applications. Cancer Radiother. 2018;22:567–80. doi:10.1016/j.canrad.2018.07.136.
  • De Ruysscher D. Combination of radiotherapy and immune treatment: first clinical data. Cancer Radiother. 2018;22:564–66. doi:10.1016/j.canrad.2018.07.128.
  • Paget S. The distribution of secondary growths in cancer of the breast 1889. Cancer Metastasis Rev. 1989;8:98–101.
  • Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30. doi:10.1038/nature21349.
  • Fousek K, Ahmed N. The evolution of T-cell therapies for solid malignancies. Clin Cancer Res. 2015;21(15):3384–92. doi:10.1158/1078-0432.CCR-14-2675.
  • Ganesan AP, Clarke J, Wood O, Garrido-Martin EM, Chee SJ, Mellows T, Samaniego-Castruita D, Singh D, Seumois G, Alzetani A, Woo E, et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol. 2017;18:940–50. doi:10.1038/ni.3775.
  • Panduro M, Benoist C, Mathis D. Tissue tregs. Annu Rev Immunol. 2016;34(1):609–33. doi:10.1146/annurev-immunol-032712-095948.
  • Ramsdell F, Ziegler SF. FOXP3 and scurfy: how it all began. Nat Rev Immunol. 2014;14(5):343–49. doi:10.1038/nri3650.
  • Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, Zhao L, Vatan L, Shao I, Szeliga W, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. 2017;18(12):1332–41. doi:10.1038/ni.3868.
  • Lavin Y, Kobayashi S, Leader A, Amir ED, Elefant N, Bigenwald C, Remark R, Sweeney R, Becker CD, Levine JH, Meinhof K, et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell. 2017;169:750–65 e17. doi:10.1016/j.cell.2017.04.014.
  • Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman W-H, Pagès F, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71(4):1263–71. doi:10.1158/0008-5472.CAN-10-2907.
  • Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who’s who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol. 2013;43:2797–809. doi:10.1002/eji.201343751.
  • Biasco L, Scala S, Basso Ricci L, Dionisio F, Baricordi C, Calabria A, Giannelli S, Cieri N, Barzaghi F, Pajno R, et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci Transl Med. 2015;7(273):273ra13. doi:10.1126/scitranslmed.3010314.
  • Cieri N, Oliveira G, Greco R, Forcato M, Taccioli C, Cianciotti B, Valtolina V, Noviello M, Vago L, Bondanza A, et al. Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation. Blood. 2015;125(18):2865–74. doi:10.1182/blood-2014-11-608539.
  • Roberto A, Castagna L, Zanon V, Bramanti S, Crocchiolo R, McLaren JE, Gandolfi S, Tentorio P, Sarina B, Timofeeva I, Santoro A, et al. Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation. Blood. 2015;125:2855–64.
  • Xiong Y, Bosselut R. CD4-CD8 differentiation in the thymus: connecting circuits and building memories. Curr Opin Immunol. 2012;24:139–45. doi:10.1016/j.coi.2012.02.002.
  • Robins E, Zheng M, Ni Q, Liu S, Liang C, Zhang B, Guo J, Zhuang Y, He Y-W, Zhu P, et al. Conversion of effector CD4+ T cells to a CD8+ MHC II-recognizing lineage. Cell Mol Immunol. 2020. doi:10.1038/s41423-019-0347-5.
  • Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, Araki K, Ahmed R. CD8 T Cell Exhaustion in Chronic Infection and Cancer: opportunities for Interventions. Annu Rev Med. 2018;69:301–18. doi:10.1146/annurev-med-012017-043208.
  • Singer A, Adoro S, Park JH. Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev Immunol. 2008;8:788–801.
  • Rothenberg EV. The chromatin landscape and transcription factors in T cell programming. Trends Immunol. 2014;35(5):195–204. doi:10.1016/j.it.2014.03.001.
  • Ciucci T, Vacchio MS, Bosselut R. A STAT3-dependent transcriptional circuitry inhibits cytotoxic gene expression in T cells. Proc Natl Acad Sci U S A. 2017;114(50):13236–41. doi:10.1073/pnas.1711160114.
  • Steinke FC, Yu S, Zhou X, He B, Yang W, Zhou B, Kawamoto H, Zhu J, Tan K, Xue -H-H, et al. TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4+ T cell fate and interact with Runx3 to silence Cd4 in CD8+ T cells. Nat Immunol. 2014;15(7):646–56. doi:10.1038/ni.2897.
  • Xing S, Shao P, Li F, Zhao X, Seo W, Wheat JC, Ramasamy S, Wang J, Li X, Peng W, et al. Tle corepressors are differentially partitioned to instruct CD8 + T cell lineage choice and identity. J Exp Med. 2018;215(8):2211–26. doi:10.1084/jem.20171514.
  • Vacchio MS, Bosselut R. What happens in the thymus does not stay in the thymus: how T cells recycle the CD4+–CD8+ lineage commitment transcriptional circuitry to control their function. J Immunol. 2016;196(12):4848–56. doi:10.4049/jimmunol.1600415.
  • Shan Q, Zeng Z, Xing S, Li F, Hartwig SM, Gullicksrud JA, Kurup SP, Van Braeckel-Budimir N, Su Y, Martin MD, Varga SM, et al. The transcription factor Runx3 guards cytotoxic CD8(+) effector T cells against deviation towards follicular helper T cell lineage. Nat Immunol. 2017;18:931–39. doi:10.1038/ni.3773.
  • Jansen CS, Prokhnevska N, Master VA, Sanda MG, Carlisle JW, Bilen MA, Cardenas M, Wilkinson S, Lake R, Sowalsky AG, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature. 2019;576(7787):465–70. doi:10.1038/s41586-019-1836-5.
  • Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019;19:133–50.
  • Hudson WH, Gensheimer J, Hashimoto M, Wieland A, Valanparambil RM, Li P, Lin JX, Konieczny BT, Im SJ, Freeman GJ, Leonard WJ, et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1(+) stem-like CD8(+) T cells during chronic infection. Immunity. 2019;51:1043–58 e4. doi:10.1016/j.immuni.2019.11.002.
  • Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, Carmona SJ, Scarpellino L, Gfeller D, Pradervand S, Luther SA, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity. 2019;50:195–211 e10. doi:10.1016/j.immuni.2018.12.021.
  • Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M, Dimeloe S, Kiialainen, A., Hanhart, J., Schill, C., Hess, C., et al. A transcriptionally and functionally distinct PD-1(+) CD8(+) T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med. 2018;24:994–1004. doi:10.1038/s41591-018-0057-z.
  • Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo, M., Alfei, F., Hofmann, M., Wieland, D., et al. T cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections. Immunity. 2016;45:415–27. doi:10.1016/j.immuni.2016.07.021.
  • Zhang J, Zheng X, Zhang Q. EglN2 positively regulates mitochondrial function in breast cancer. Mol Cell Oncol. 2016;3:e1120845. doi:10.1080/23723556.2015.1120845.
  • Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015;6:7–17.
  • Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20(3):326–36. doi:10.1038/s41590-019-0312-6.
  • Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, Bjorgaard, S L., Hammond, M R., Vitzthum, H., Blackmon, S M., et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun. 2017;8:1136. doi:10.1038/s41467-017-01062-w.
  • Kurtulus S, Madi A, Escobar G, Klapholz M, Nyman J, Christian E, Pawlak, M., Dionne, D., Xia, J., Rozenblatt-Rosen, O., et al. Checkpoint blockade immunotherapy induces dynamic changes in PD-1(-)CD8(+) tumor-infiltrating T cells. Immunity. 2019;50:181–94 e6. doi:10.1016/j.immuni.2018.11.014.
  • Zhang L, Yu X, Zheng L, Zhang Y, Li Y, Fang Q, Gao, R., Kang, B., Zhang, Q., Huang, J Y., et al. Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature. 2018;564:268–72.
  • Brummelman J, Mazza EMC, Alvisi G, Colombo FS, Grilli A, Mikulak J, Mavilio D, Alloisio M, Ferrari F, Lopci E, et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors. J Exp Med. 2018;215(10):2520–35. doi:10.1084/jem.20180684.
  • Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537(7620):417–21. doi:10.1038/nature19330.
  • Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hofmann M, Thimme R, et al. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 2017;8(1):15050. doi:10.1038/ncomms15050.
  • Gullicksrud JA, Li F, Xing S, Zeng Z, Peng W, Badovinac VP, Harty, J T., Xue, H-H Differential requirements for Tcf1 long isoforms in CD8(+) and CD4(+) T cell responses to acute viral infection. J Immunol. 2017;199:911–19. doi:10.4049/jimmunol.1700595.
  • McNichol L, Lund C, Rosen T, Gray M. Medical adhesives and patient safety: state of the science: consensus statements for the assessment, prevention, and treatment of adhesive-related skin injuries. Orthop Nurs. 2013;32(5):267–81. doi:10.1097/NOR.0b013e3182a39caf.
  • Wang X, Zheng B, Lu X, Bai R, Feng L, Wang Q, Zhao, Y., He, S., Preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer: meta-analysis with trial sequential analysis of long-term survival data. PLoS One. 2018;13:e0200142. doi:10.1371/journal.pone.0200142.
  • Tang Y, Jin J, Zhu Y, Liu S, Yuan X, Wang W, Wang X, Zhang Z, Tian Y, Gao Y, et al. Consensus and contouring atlas for the delineation of clinical target volume in pre-/post-operative image-guided intensity mdulated radiotherapy for rectal cancer. J Clin Surg. 2018;27:227–234.
  • Tao J, Wang G. Prognostic factors of pathological complete remission after neoadjuvant radiotherapy and chemotherapy for locally advanced rectal cancer. J Clin Surg. 2018;26:756–59.
  • Marciscano AE, Walker JM, McGee HM, Kim MM, Kunos CA, Monjazeb AM, Shiao, S L., Tran, P T., Ahmed, M M. Incorporating radiation oncology into immunotherapy: proceedings from the ASTRO-SITC-NCI immunotherapy workshop. J Immunother Cancer. 2018;6:6. doi:10.1186/s40425-018-0317-y.
  • Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14:365–79.
  • Diegeler S, Hellweg CE. Intercellular communication of tumor cells and immune cells after exposure to different ionizing radiation qualities. Front Immunol. 2017;8:664. doi:10.3389/fimmu.2017.00664.
  • Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the Game in immunotherapy. Trends in Cancer. 2016;2(6):286–94. doi:10.1016/j.trecan.2016.05.002.
  • Siva S, MacManus MP, Martin RF, Martin OA. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett. 2015;356(1):82–90. doi:10.1016/j.canlet.2013.09.018.
  • Strom T, Harrison LB, Giuliano AR, Schell MJ, Eschrich SA, Berglund A, Fulp W, Thapa R, Coppola D, Kim S, et al. Tumour radiosensitivity is associated with immune activation in solid tumours. Eur J Cancer. 2017;84:304–14. doi:10.1016/j.ejca.2017.08.001.
  • Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 2015;1:1325–32. doi:10.1001/jamaoncol.2015.2756.
  • Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, Francica BJ, Velarde E, Deweese, T L., Drake, C G. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res. 2015;3:345–55. doi:10.1158/2326-6066.CIR-14-0196.
  • Ceccaldi R, Rondinelli B, D’Andrea AD. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 2016;26:52–64. doi:10.1016/j.tcb.2015.07.009.
  • Chao Y, Xu L, Liang C, Feng L, Xu J, Dong Z, Tian, L., Yi, X., Yang, K., Liu, Z., et al. Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumour responses. Nat Biomed Eng. 2018;2:611–21. doi:10.1038/s41551-018-0262-6.
  • Wu Q, Allouch A, Martins I, Brenner C, Modjtahedi N, Deutsch E, Perfettini, J-L. Modulating both tumor cell death and innate immunity is essential for improving radiation therapy effectiveness. Front Immunol. 2017;8:613. doi:10.3389/fimmu.2017.00613.
  • Min Y, Roche KC, Tian S, Eblan MJ, McKinnon KP, Caster JM, Chai S, Herring LE, Zhang L, Zhang T, et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat Nanotechnol. 2017;12(9):877–82. doi:10.1038/nnano.2017.113.
  • Hu ZI, McArthur HL, Ho AY. The abscopal effect of radiation therapy: what is it and how can we use it in breast cancer? Curr Breast Cancer Rep. 2017;9(1):45–51. doi:10.1007/s12609-017-0234-y.
  • Onishi M, Okonogi N, Oike T, Yoshimoto Y, Sato H, Suzuki Y, Kamada, T., Nakano, T High linear energy transfer carbon-ion irradiation increases the release of the immune mediator high mobility group box 1 from human cancer cells. J Radiat Res. 2018;59:541–46. doi:10.1093/jrr/rry049.
  • Huang CY, Chiang SF, Ke TW, Chen TW, Lan YC, You YS, Shiau, A-C., Chen, W.T.L., Chao, K.S.C. Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy. Cancer Immunol Immunother. 2018;67:551–62. doi:10.1007/s00262-017-2109-5.
  • Dosset M, Vargas TR, Lagrange A, Boidot R, Vegran F, Roussey A, Chalmin F, Dondaine L, Paul C, Marie-Joseph EL, et al. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. Oncoimmunology. 2018;7(6):e1433981. doi:10.1080/2162402X.2018.1433981.
  • Liu P, Zhao L, Pol J, Levesque S, Petrazzuolo A, Pfirschke C, Engblom C, Rickelt S, Yamazaki T, Iribarren K, et al. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat Commun. 2019;10(1):1486. doi:10.1038/s41467-019-09415-3.
  • Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–77. doi:10.1038/nature14292.
  • Dillon MT, Bergerhoff KF, Pedersen M, Whittock H, Crespo-Rodriguez E, Patin EC, Pearson A, Smith HG, Paget JTE, Patel RR, et al. ATR inhibition potentiates the radiation-induced inflammatory tumor microenvironment. Clin Cancer Res. 2019;25(11):3392–403. doi:10.1158/1078-0432.CCR-18-1821.
  • Sen T, Rodriguez BL, Chen L, Corte CMD, Morikawa N, Fujimoto J, Cristea S, Nguyen T, Diao L, Li L, et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 2019;9(5):646–61. doi:10.1158/2159-8290.CD-18-1020.
  • Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, Inghirami G, Coleman CN, Formenti SC, Demaria S, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8(1):15618. doi:10.1038/ncomms15618.
  • Mardjuki RE, Carozza JA, Li L. Development of cGAMP-Luc, a sensitive and precise coupled enzyme assay to measure cGAMP in complex biological samples. J Biol Chem. 2020;295(15):4881–92. doi:10.1074/jbc.RA119.012170.
  • Marcus A, Mao AJ, Lensink-Vasan M, Wang L, Vance RE, Raulet DH. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity. 2018;49(4):754–63 e4. doi:10.1016/j.immuni.2018.09.016.
  • Diamond JM, Vanpouille-Box C, Spada S, Rudqvist NP, Chapman JR, Ueberheide BM, Pilones, K A., Sarfraz, Y., Formenti, S C., Demaria, S., et al. Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs. Cancer Immunol Res. 2018;6:910–20. doi:10.1158/2326-6066.CIR-17-0581.
  • Gullo I, Carvalho J, Martins D, Lemos D, Monteiro AR, Ferreira M, Das K, Tan P, Oliveira C, Carneiro F, Oliveira P., et al. The transcriptomic landscape of gastric cancer: insights into epstein-barr virus infected and microsatellite unstable tumors. Int J Mol Sci. 2018;19(7):2079.
  • Chiang SF, Huang CY, Ke TW, Chen TW, Lan YC, You YS, Chen, W.T.L., Chao, K.S.C. Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers.Cancer Immunol Immunother. 2019;68:283–96. doi:10.1007/s00262-018-2275-0.
  • Wang Q, Wu X. Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment. Int Immunopharmacol. 2017;46:210–19. doi:10.1016/j.intimp.2017.03.015.
  • Jiang W, Chan CK, Weissman IL, Kim BYS, Hahn SM. Immune priming of the tumor microenvironment by radiation. Trends in Cancer. 2016;2(11):638–45. doi:10.1016/j.trecan.2016.09.007.
  • Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548(7668):466–70. doi:10.1038/nature23470.
  • Wang Z, Chen J, Hu J, Zhang H, Xu F, He W, Wang, X., Li, M., Lu, W., Zeng, G., et al. cGAS/STING axis mediates a topoisomerase II inhibitor-induced tumor immunogenicity. J Clin Invest. 2019;130:4850–62. doi:10.1172/JCI127471.
  • Billiard F, Buard V, Benderitter M, Linard C. Abdominal gamma-radiation induces an accumulation of function-impaired regulatory T cells in the small intestine. Int J Radiat Oncol Biol Phys. 2011;80:869–76. doi:10.1016/j.ijrobp.2010.12.041.
  • Mondini M, Loyher PL, Hamon P, Gerbe de Thore 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 TNFalpha-mediated resistance. Cancer Immunol Res. 2019;7:376–87. doi:10.1158/2326-6066.CIR-18-0633.
  • de Leve S, Wirsdorfer F, Jendrossek V. Targeting the immunomodulatory CD73/adenosine system to improve the therapeutic gain of radiotherapy. Front Immunol. 2019;10:698.
  • Baird JR, Friedman D, Cottam B, Dubensky TW Jr., Kanne DB, Bambina S, Bahjat, K., Crittenden, M R., Gough, M J. Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors. Cancer Res. 2016;76:50–61. doi:10.1158/0008-5472.CAN-14-3619.
  • Benci JL, Xu B, Qiu Y, Wu TJ, Dada H, Twyman-Saint Victor C, Cucolo L, Lee DSM, Pauken KE, Huang AC, et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell. 2016;167(6):1540–54 e12. doi:10.1016/j.cell.2016.11.022.
  • Liu H, Golji J, Brodeur LK, Chung FS, Chen JT, deBeaumont RS, Bullock CP, Jones MD, Kerr G, Li L, et al. Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat Med. 2019;25(1):95–102. doi:10.1038/s41591-018-0302-5.
  • Su C, Zhang B, Liu W, Zheng H, Sun L, Tong J, Wang T, Jiang X, Liang H, Xue L, et al. High extracellular pressure promotes gastric cancer cell adhesion, invasion, migration and suppresses gastric cancer cell differentiation. Oncol Rep. 2016;36(2):1048–54. doi:10.3892/or.2016.4841.
  • Jerrell RJ, Parekh A. Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2. Biomaterials. 2016;84:119–29. doi:10.1016/j.biomaterials.2016.01.028.
  • Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 2004;64(12):4328–37. doi:10.1158/0008-5472.CAN-04-0073.
  • Dovedi SJ, Cheadle EJ, Popple AL, Poon E, Morrow M, Stewart R, Yusko EC, Sanders CM, Vignali M, Emerson RO, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res. 2017;23(18):5514–26. doi:10.1158/1078-0432.CCR-16-1673.
  • Wang H, Hu S, Chen X, Shi H, Chen C, Sun L, Chen, Z J. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc Natl Acad Sci U S A. 2017;114:1637–42. doi:10.1073/pnas.1621363114.
  • Eckert F, Gaipl US, Niedermann G, Hettich M, Schilbach K, Huber SM, Zips D. Beyond checkpoint inhibition - Immunotherapeutical strategies in combination with radiation. Clin Transl Radiat Oncol. 2017;2:29–35. doi:10.1016/j.ctro.2016.12.006.
  • Wang L, Shureiqi I, Stroehlein JR, Wei D. Novel and emerging innate immune therapeutic targets for pancreatic cancer. Expert Opin Ther Targets. 2018;22:977–81. doi:10.1080/14728222.2018.1538361.
  • Iurescia S, Fioretti D, Rinaldi M. Targeting cytosolic nucleic acid-sensing pathways for cancer immunotherapies. Front Immunol. 2018;9:711. doi:10.3389/fimmu.2018.00711.
  • Rutkowski J, Slebioda T, Kmiec Z, Zaucha R. Changes in systemic immune response after stereotactic ablative radiotherapy. Preliminary results of a prospective study in patients with early lung cancer. Pol Arch Intern Med. 2017;127:245–53.
  • Wang L, Wildt KF, Zhu J, Zhang X, Feigenbaum L, Tessarollo L, Paul, W E., Fowlkes, B J., Bosselut, R. Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4(+) T cells. Nat Immunol. 2008;9:1122–30. doi:10.1038/ni.1647.
  • Philips GK, Atkins M. Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. Int Immunol. 2015;27(1):39–46. doi:10.1093/intimm/dxu095.
  • Ding Y, Jiang J. Antitumor immune mechanism of programmed death receptor-1/ligand 1 monoclonal antibody combined with radiotherapy. Chin J Exp Surg. 2018;35:2362–64.
  • Teixido C, Gonzalez-Cao M, Karachaliou N, Rosell R. Predictive factors for immunotherapy in melanoma. Ann Transl Med. 2015;3:208.
  • Boger C, Behrens HM, Mathiak M, Kruger S, Kalthoff H, Rocken C. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget. 2016;7:24269–83.
  • Gao Y, Li S, Xu D, Chen S, Cai Y, Jiang W, Zhang X, Sun J, Wang K, Chang B, et al. Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma. Chin J Cancer. 2017;36:61. doi:10.1186/s40880-017-0226-3.
  • Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, Piperdi, B., Mehnert, J M. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35:3823–29. doi:10.1200/JCO.2017.72.5069.
  • Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. doi:10.1056/NEJMoa1412082.
  • Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, Zahurak M, Yang SC, Jones DR, Broderick S, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976–86. doi:10.1056/NEJMoa1716078.
  • Ratti M, Lampis A, Hahne JC, Passalacqua R, Valeri N. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci. 2018;75(22):4151–62. doi:10.1007/s00018-018-2906-9.
  • Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, Liu, X Q., Sher, X., Jung, H., Lee, M., et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24:1449–58. doi:10.1038/s41591-018-0101-z.
  • Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen HZ, Reeser JW, Yu L, Roychowdhury S. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017:PO.17.00073.
  • O’Donnell JS, Long GV, Scolyer RA, Teng MW, Smyth MJ. Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev. 2017;52:71–81. doi:10.1016/j.ctrv.2016.11.007.
  • Liu Y, Li H, Zhao D, Cheng Y. Differential expression of MMR and PD-L1 in stage II postoperative colorectal cancer. Chin J Colorectal Dis. 2018;7:562–66.
  • Mitteldorf C, Berisha A, Pfaltz MC, Broekaert SMC, Schon MP, Kerl K, Kempf, W. Tumor microenvironment and checkpoint molecules in primary cutaneous diffuse large B-cell lymphoma-new therapeutic targets. Am J Surg Pathol. 2017;41:998–1004. doi:10.1097/PAS.0000000000000851.
  • Liu F, Chang L, Hu J. Activating transcription factor 6 regulated cell growth, migration and inhibiteds cell apoptosis and autophagy via MAPK pathway in cervical cancer. J Reprod Immunol. 2020;139:103120. doi:10.1016/j.jri.2020.103120.
  • Zhuang Y, Liu C, Liu J, Li G. resistance mechanism of PD-1/PD-L1 blockade in the cancer-immunity cycle. Onco Targets Ther. 2020;13:83–94. doi:10.2147/OTT.S239398.
  • Garcia AJ, Ruscetti M, Arenzana TL, Tran LM, Bianci-Frias D, Sybert E, Priceman SJ, Wu L, Nelson PS, Smale ST, et al. Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression. Mol Cell Biol. 2014;34(11):2017–28. doi:10.1128/MCB.00090-14.
  • Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, Zhang C, Liang X, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202–16. doi:10.1158/2159-8290.CD-15-0283.
  • Rimawi MF, De Angelis C, Contreras A, Pareja F, Geyer FC, Burke KA, Herrera S, Wang T, Mayer IA, Forero A, et al. Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat. 2018;167(3):731–40. doi:10.1007/s10549-017-4533-9.
  • Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273–91. doi:10.1038/nrclinonc.2018.28.
  • Costa RLB, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018;169(3):397–406. doi:10.1007/s10549-018-4697-y.
  • Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik T, Lavender N, Johnson AC, McClain C, et al. PI3K inhibition reduces mammary tumor growth and facilitates antitumor immunity and Anti-PD1 responses. Clin Cancer Res. 2017;23(13):3371–84. doi:10.1158/1078-0432.CCR-16-2142.
  • Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20(1):25–39. doi:10.1038/s41577-019-0218-4.
  • Jimenez-Sanchez A, Memon D, Pourpe S, Veeraraghavan H, Li Y, Vargas HA, Gill MB, Park KJ, Zivanovic O, Konner J, et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell. 2017;170(5):927–38 e20. doi:10.1016/j.cell.2017.07.025.
  • Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461–73.
  • Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, et al. Mutations associated with acquired resistance to PD-1 blockade in Melanoma. N Engl J Med. 2016;375(9):819–29. doi:10.1056/NEJMoa1604958.
  • Wang Y, Wang L. miR-34a attenuates glioma cells progression and chemoresistance via targeting PD-L1. Biotechnol Lett. 2017;39(10):1485–92. doi:10.1007/s10529-017-2397-z.
  • Ishibashi M, Tamura H, Sunakawa M, Kondo-Onodera A, Okuyama N, Hamada Y, Moriya K, Choi I, Tamada K, Inokuchi K, et al. Myeloma drug resistance induced by binding of myeloma B7-H1 (PD-L1) to PD-1. Cancer Immunol Res. 2016;4(9):779–88. doi:10.1158/2326-6066.CIR-15-0296.
  • Sucker A, Zhao F, Pieper N, Heeke C, Maltaner R, Stadtler N, Real, B., Bielefeld, N., Howe, S., Weide, B., et al. Acquired IFNgamma resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nat Commun. 2017;8:15440. doi:10.1038/ncomms15440.
  • Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, Grasso CS, Hugo W, Sandoval S, Torrejon DY, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7(2):188–201. doi:10.1158/2159-8290.CD-16-1223.
  • Bai J, Gao Z, Li X, Dong L, Han W, Nie J. Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget. 2017;8(66):110693–707. doi:10.18632/oncotarget.22690.
  • Wang H, Fu C, Du J, Wang H, He R, Yin X, Li H, Li X, Wang H, Li K, et al. Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells. J Exp Clin Cancer Res. 2020;39(1):29. doi:10.1186/s13046-020-1536-x.
  • Cicenas J, Kalyan K, Sorokinas A, Jatulyte A, Valiunas D, Kaupinis A, Valius, M. Highlights of the latest advances in research on CDK inhibitors. Cancers (Basel). 2014;6:2224–42. doi:10.3390/cancers6042224.
  • Schaer DA, Beckmann RP, Dempsey JA, Huber L, Forest A, Amaladas N, Li Y, Wang YC, Rasmussen ER, Chin D, et al. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep. 2018;22(11):2978–94. doi:10.1016/j.celrep.2018.02.053.
  • Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–75. doi:10.1038/nature23465.
  • Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, Chhabra S, Huang W, Liu H, Aref AR, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8(2):216–33. doi:10.1158/2159-8290.CD-17-0915.
  • Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, Leeson, R., Kanodia, A., Mei, S., Lin, J-R., et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018;175:984–97 e24. doi:10.1016/j.cell.2018.09.006.
  • Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61–68. doi:10.1016/j.canlet.2016.01.043.
  • Marty R, Kaabinejadian S, Rossell D, Slifker MJ, van de Haar J, Engin HB, de Prisco N, Ideker T, Hildebrand WH, Font-Burgada J, et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell. 2017;171(6):1272–83 e15. doi:10.1016/j.cell.2017.09.050.
  • Huang AC, Orlowski RJ, Xu X, Mick R, George SM, Yan PK, Manne S, Kraya AA, Wubbenhorst B, Dorfman L, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019;25(3):454–61. doi:10.1038/s41591-019-0357-y.
  • McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, Birkbak NJ, Veeriah S, Van Loo P, Herrero J, et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell. 2017;171(6):1259–71 e11. doi:10.1016/j.cell.2017.10.001.
  • Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500–01. doi:10.1056/NEJMc1713444.
  • Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, Zhang, T., Adleff, V., Phallen, J., Wali, N., et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 2017;7:264–76. doi:10.1158/2159-8290.CD-16-0828.
  • Thommen DS, Schreiner J, Muller P, Herzig P, Roller A, Belousov A, Umana, P., Pisa, P., Klein, C., Bacac, M., et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res. 2015;3:1344–55. doi:10.1158/2326-6066.CIR-15-0097.
  • Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi, L., Redig, A J., Rodig, S J., Asahina, H., et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501. doi:10.1038/ncomms10501.
  • Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015;6:418. doi:10.3389/fimmu.2015.00418.
  • Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, Zaretsky JM, Sun L, Hugo W, Wang X, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19(6):1189–201. doi:10.1016/j.celrep.2017.04.031.
  • Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci. 2017;24:26. doi:10.1186/s12929-017-0329-9.
  • Anderson ES, Postow MA, Wolchok JD, Young RJ, Ballangrud A, Chan TA, Yamada, Y., Beal, K. Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. J Immunother Cancer. 2017;5:76. doi:10.1186/s40425-017-0282-x.
  • Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon, E B., Lee, P. 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. 2017;18:895–903. doi:10.1016/S1470-2045(17)30380-7.
  • De Ruysscher D. Radiotherapy and PD-L1 inhibition in metastatic NSCLC. Lancet Oncol. 2017;18(7):840–42. doi:10.1016/S1470-2045(17)30354-6.
  • Maity A, Mick R, Huang AC, George SM, Farwell MD, Lukens JN, Berman AT, Mitchell TC, Bauml J, Schuchter LM, et al. A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours. Br J Cancer. 2018;119(10):1200–07. doi:10.1038/s41416-018-0281-9.
  • Theelen W, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts J, Dumoulin, D W., Bahce, I., Niemeijer, A.L.N., de Langen, A J., et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol. 2019. doi:10.1001/jamaoncol.2019.1478.
  • Shevtsov M, Sato H, Multhoff G, Shibata A. Novel approaches to improve the efficacy of immuno-radiotherapy. Front Oncol. 2019;9:156. doi:10.3389/fonc.2019.00156.
  • Sato H, Okonogi N, Nakano T. Rationale of combination of anti-PD-1/PD-L1 antibody therapy and radiotherapy for cancer treatment. Int J Clin Oncol. 2020;25(5):801–09. doi:10.1007/s10147-020-01666-1.
  • Iijima M, Okonogi N, Nakajima NI, Morokoshi Y, Kanda H, Yamada T, Kobayashi Y, Banno K, Wakatsuki M, Yamada S, et al. Significance of PD-L1 expression in carbon-ion radiotherapy for uterine cervical adeno/adenosquamous carcinoma. J Gynecol Oncol. 2020;31(2):e19. doi:10.3802/jgo.2020.31.e19.
  • Permata TBM, Hagiwara Y, Sato H, Yasuhara T, Oike T, Gondhowiardjo S, Held, K D., Nakano, T., Shibata, A. Base excision repair regulates PD-L1 expression in cancer cells. Oncogene. 2019;38:4452–66. doi:10.1038/s41388-019-0733-6.
  • Ribas A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 2015;5(9):915–19. doi:10.1158/2159-8290.CD-15-0563.
  • Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu, Y-X. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–95. doi:10.1172/JCI67313.
  • Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545(7652):60–65. doi:10.1038/nature22079.
  • Kordbacheh T, Honeychurch J, Blackhall F, Faivre-Finn C, Illidge T. Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms. Ann Oncol. 2018;29(2):301–10. doi:10.1093/annonc/mdx790.
  • Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin. 2017;67:65–85.
  • Takahashi Y, Yasui T, Tamari K, Minami K, Otani K, Isohashi F, Seo Y, Kambe R, Koizumi M, Ogawa K, et al. Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma. PLoS One. 2017;12(12):e0189697. doi:10.1371/journal.pone.0189697.
  • Bockel S, Antoni D, Deutsch E, Mornex F. [Immunotherapy and radiotherapy]. Cancer Radiother. 2017;21:244–55. doi:10.1016/j.canrad.2016.12.005.
  • Walle T, Martinez Monge R, Cerwenka A, Ajona D, Melero I, Lecanda F. Radiation effects on antitumor immune responses: current perspectives and challenges. Ther Adv Med Oncol. 2018;10:1758834017742575. doi:10.1177/1758834017742575.
  • Gong J, Le TQ, Massarelli E, Hendifar AE, Tuli R. Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. J Immunother Cancer. 2018;6:46.
  • Cao Y, Li W, Wang Z, Pang H. Potential and unsolved problems of anti-PD-1/PD-L1 therapy combined with radiotherapy. Tumori. 2020;300891620940382. [published online ahead of print, 2020 Jul 31].
  • Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, Stratford IJ, Poon E, Morrow M, Stewart R, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458–68. doi:10.1158/0008-5472.CAN-14-1258.
  • Chen L, Douglass J, Kleinberg L, Ye X, Marciscano AE, Forde PM, Brahmer J, Lipson E, Sharfman W, Hammers H, et al. Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol Biol Phys. 2018;100(4):916–25. doi:10.1016/j.ijrobp.2017.11.041.
  • Jabbour SK, Berman AT, Decker RH, Lin Y, Feigenberg SJ, Gettinger SN, Aggarwal, C., Langer, C J., Simone, C B., Bradley, J D., et al. Phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non-small cell lung cancer: a nonrandomized controlled Trial. JAMA Oncol. 2020;6:848–55.
  • Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919–29. doi:10.1056/NEJMoa1709937.
  • Ahmed KA, Stallworth DG, Kim Y, Johnstone PA, Harrison LB, Caudell JJ, Yu HHM, Etame AB, Weber JS, Gibney GT, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016;27(3):434–41. doi:10.1093/annonc/mdv622.
  • Kotecha R, Kim JM, Miller JA, Juloori A, Chao ST, Murphy ES, Peereboom DM, Mohammadi AM, Barnett GH, Vogelbaum MA, et al. The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis. Neuro Oncol. 2019;21(8):1060–68. doi:10.1093/neuonc/noz046.
  • Lim SH, Hong M, Ahn S, Choi YL, Kim KM, Oh D, Ahn, Y.C., Jung, S.-H., Ahn, M.-J., Park, K., et al. Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. Eur J Cancer. 2016;52:1–9. doi:10.1016/j.ejca.2015.09.019.
  • Chen TW, Huang KC, Chiang SF, Chen WT, Ke TW, Chao KSC. Prognostic relevance of programmed cell death-ligand 1 expression and CD8+ TILs in rectal cancer patients before and after neoadjuvant chemoradiotherapy. J Cancer Res Clin Oncol. 2019;145:1043–53. doi:10.1007/s00432-019-02874-7.
  • Xie G, Gu D, Zhang L, Chen S, Wu D. A rapid and systemic complete response to stereotactic body radiation therapy and pembrolizumab in a patient with metastatic renal cell carcinoma. Cancer Biol Ther. 2017;18(8):547–51. doi:10.1080/15384047.2017.1345389.
  • Gong X, Li X, Jiang T, Xie H, Zhu Z, Zhou F, Zhou, C. Combined Radiotherapy and anti-PD-L1 antibody synergistically enhances antitumor effect in non-small cell lung cancer. J Thorac Oncol. 2017;12:1085–97. doi:10.1016/j.jtho.2017.04.014.
  • Yuan Z, Fromm A, Ahmed KA, Grass GD, Yang GQ, Oliver DE, Dilling, T J., Antonia, S J., Perez, B A. Radiotherapy rescue of a nivolumab-refractory immune response in a patient with PD-L1-negative metastatic squamous cell carcinoma of the lung. J Thorac Oncol. 2017;12:e135–e6. doi:10.1016/j.jtho.2017.04.029.
  • Sharabi A, Kim SS, Kato S, Sanders PD, Patel SP, Sanghvi P, Weihe E, Kurzrock R. Exceptional response to nivolumab and stereotactic body radiation therapy (SBRT) in neuroendocrine cervical carcinoma with high tumor mutational burden: management considerations from the center for personalized cancer therapy at UC San Diego moores cancer center. Oncologist. 2017;22:631–37.
  • Michot JM, Mazeron R, Dercle L, Ammari S, Canova C, Marabelle A, Rose, S., Rubin, E., Deutsch, E., Soria, J-C., et al. Abscopal effect in a Hodgkin lymphoma patient treated by an anti-programmed death 1 antibody. Eur J Cancer. 2016;66:91–94. doi:10.1016/j.ejca.2016.06.017.
  • Yu Y, Zeng D, Ou Q, Liu S, Li A, Chen Y, Lin, D., Gao, Q., Zhou, H., Liao, W., et al. Association of survival and immune-related biomarkers with immunotherapy in patients with non-small cell lung cancer: a meta-analysis and individual patient-level analysis. JAMA Netw Open. 2019;2:e196879. doi:10.1001/jamanetworkopen.2019.6879.
  • Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US food and drug administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):278. doi:10.1186/s40425-019-0768-9.
  • Sampath S, Rahmanuddin S, Sahoo P, Frankel P, Boswell S, Wong J, Rotter, A., Rockne, R., Wong, J., Park, J M., et al. Change in apparent diffusion coefficient is associated with local failure after stereotactic body radiation therapy for non-small cell lung cancer: a prospective clinical trial. Int J Radiat Oncol Biol Phys. 2019;105(3):659–63. doi:10.1016/j.ijrobp.2019.06.2536.
  • Ahn HK, Lee H, Kim SG, Hyun SH. Pre-treatment (18)F-FDG PET-based radiomics predict survival in resected non-small cell lung cancer. Clin Radiol. 2019;74:467–73. doi:10.1016/j.crad.2019.02.008.
  • Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. doi:10.1056/NEJMoa1500596.
  • Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13. doi:10.1126/science.aan6733.
  • Luo H, Ge H, Cui Y, Zhang J, Fan R, Zheng A, Zheng, X., Sun, Y. Systemic inflammation biomarkers predict survival in patients of early stage non-small cell lung cancer treated with stereotactic ablative radiotherapy - a single center experience. J Cancer. 2018;9:182–88. doi:10.7150/jca.21703.
  • Yamaguchi O, Kaira K, Hashimoto K, Mouri A, Miura Y, Shiono A, Nishihara, F., Murayama, Y., Noda, S-E., Kato, S., et al. Radiotherapy is an independent prognostic marker of favorable prognosis in non-small cell lung cancer patients after treatment with the immune checkpoint inhibitor, nivolumab. Thorac Cancer. 2019;10:992–1000. doi:10.1111/1759-7714.13044.
  • Mauclet C, Duplaquet F, Pirard L, Rondelet B, Dupont M, Pop-Stanciu C, Vander Borght T, Remmelink M, D’Haene N, Lambin S, et al. Complete tumor response of a locally advanced lung large-cell neuroendocrine carcinoma after palliative thoracic radiotherapy and immunotherapy with nivolumab. Lung Cancer. 2019;128:53–56. doi:10.1016/j.lungcan.2018.12.006.
  • Komori T, Otsuka A, Irie H, Horiguchi A, Honda T, Kabashima K. Drastic effect on giant lung metastatic melanoma by sequential administration of nivolumab with ipilimumab/radiation combination therapy. J Dermatol. 2018;45(1):e7–e8. doi:10.1111/1346-8138.14078.

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