PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation

References

• Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17:956–65. doi:10.1016/S1470-2045(16)30066-3. PMID:27247226
   PubMed Web of Science ®Google Scholar
• Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375:1856–67. doi:10.1056/NEJMoa1602252. PMID:27718784
   PubMed Web of Science ®Google Scholar
• Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064–74. doi:10.1158/1078-0432.CCR-13-3271. PMID:24714771
   PubMed Web of Science ®Google Scholar
• Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J, Horiot JC, Le Maître A, Pajak TF, Poulsen MG, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet. 2006;368:843–54. doi:10.1016/S0140-6736(06)69121-6. PMID:16950362
   PubMed Web of Science ®Google Scholar
• Twyman-Saint/sVictor 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;520:373–7. doi:10.1038/nature14292. PMID:25754329
   PubMed Web of Science ®Google Scholar
• Hodge JW, Sharp HJ, Gameiro SR. Abscopal regression of antigen disparate tumors by antigen cascade after systemic tumor vaccination in combination with local tumor radiation. Cancer Biother Radiopharm. 2012;27:12–22. doi:10.1089/cbr.2012.1202. PMID:22283603
   PubMed Web of Science ®Google Scholar
• 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;64:4328–37. doi:10.1158/0008-5472.CAN-04-0073. PMID:15205348
   PubMed Web of Science ®Google Scholar
• Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li XD, Mauceri H, Beckett M, Darga T, et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity. 2014;41:843–52. doi:10.1016/j.immuni.2014.10.019. PMID:25517616
   PubMed Web of Science ®Google Scholar
• Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, Inghirami G, Coleman CN, Formenti SC, Demaria S. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. doi:10.1038/ncomms15618. PMID:28598415
   PubMed Web of Science ®Google Scholar
• Campian JL, Sarai G, Ye X, Marur S, Grossman SA. Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer. Head Neck. 2014;36:1747–53. doi:10.1002/hed.23535. PMID:24174270
   PubMed Web of Science ®Google Scholar
• Kuo P, Bratman SV, Shultz DB, von Eyben R, Chan C, Wang Z, Say C, Gupta A, Loo BW Jr, Giaccia AJ, et al. Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clin Cancer Res. 2014;20:5558–69. doi:10.1158/1078-0432.CCR-14-1138. PMID:25189484
   PubMed Web of Science ®Google Scholar
• Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11:728–34. PMID:15701862
   PubMed Web of Science ®Google Scholar
• Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–95. doi:10.1172/JCI67313. PMID:24382348
   PubMed Web of Science ®Google Scholar
• Ruocco MG, Pilones KA, Kawashima N, Cammer M, Huang J, Babb JS, Liu M, Formenti SC, Dustin ML, Demaria S. Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects. J Clin Invest. 2012;122:3718–30. doi:10.1172/JCI61931. PMID:22945631
   PubMed Web of Science ®Google Scholar
• Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379–88. doi:10.1158/1078-0432.CCR-09-0265. PMID:19706802
   PubMed Web of Science ®Google Scholar
• Davis RJ, Moore EC, Clavijo PE, Friedman J, Cash HA, Chen Z, Silvin C, Van Waes C, Allen C. Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid derived suppressor cells with a selective inhibitor of PI3Kdelta/gamma. Cancer Res. 2017;77(10):2607–19. doi:10.1158/0008-5472.CAN-16-2534. PMID:28364000
   PubMed Web of Science ®Google Scholar
• Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol. 2008;180:3132–9. doi:10.4049/jimmunol.180.5.3132. PMID:18292536
   PubMed Web of Science ®Google Scholar
• Garnett CT, Palena C, Chakraborty M, Tsang KY, Schlom J, Hodge JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res. 2004;64:7985–94. doi:10.1158/0008-5472.CAN-04-1525. PMID:15520206
   PubMed Web of Science ®Google Scholar
• Vilain RE, Menzies AM, Wilmott JS, Kakavand H, Madore J, Guminski A, Liniker E, Kong BY, Cooper AJ, Howle JR, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res. 2017;23(17):5024–33. doi:10.1158/1078-0432.CCR-16-0698. PMID:28512174
   PubMed Web of Science ®Google Scholar
• Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203:1259–71. doi:10.1084/jem.20052494. PMID:16636135
   PubMed Web of Science ®Google Scholar
• 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;74:5458–68. doi:10.1158/0008-5472.CAN-14-1258. PMID:25274032
   PubMed Web of Science ®Google Scholar
• Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget. 2014;5:403–16. doi:10.18632/oncotarget.1719. PMID:24480782
   PubMed Web of Science ®Google Scholar
• Heylmann D, Rodel F, Kindler T, Kaina B. Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells. Biochim Biophys Acta. 2014;1846:121–9. PMID:24797212
   PubMed Web of Science ®Google Scholar
• Crocenzi T, Cottam B, Newell P, Wolf RF, Hansen PD, Hammill C, Solhjem MC, To YY, Greathouse A, Tormoen G, et al. A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma. J Immunother Cancer. 2016;4:45. doi:10.1186/s40425-016-0149-6. PMID:27532020
   PubMed Web of Science ®Google Scholar
• Clavijo PE, Moore EC, Chen J, Davis RJ, Friedman J, Kim Y, Van Waes C, Chen Z, Allen CT. Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells. Oncotarget. 2017;8(34):55804–20. PMID:28915554
   PubMed Web of Science ®Google Scholar
• Filatenkov A, Baker J, Mueller AM, Kenkel J, Ahn GO, Dutt S, Zhang N, Kohrt H, Jensen K, Dejbakhsh-Jones S, et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res. 2015;21:3727–39. doi:10.1158/1078-0432.CCR-14-2824. PMID:25869387
   PubMed Web of Science ®Google Scholar
• Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, Kaplan RN, Mackall CL. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014;6:237ra67. doi:10.1126/scitranslmed.3007974. PMID:24848257
   PubMed Web of Science ®Google Scholar
• Davis RJ, Van Waes C, Allen CT. Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer. Oral Oncol. 2016;58:59–70. doi:10.1016/j.oraloncology.2016.05.002. PMID:27215705
   PubMed Web of Science ®Google Scholar
• Zhang B, Karrison T, Rowley DA, Schreiber H. IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers. J Clin Invest. 2008;118:1398–404. doi:10.1172/JCI33522. PMID:18317595
   PubMed Web of Science ®Google Scholar
• Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012;83:1306–10. doi:10.1016/j.ijrobp.2011.09.049. PMID:22208977
   PubMed Web of Science ®Google Scholar
• Rodriguez-Ruiz ME, Rodriguez I, Garasa S, Barbes B, Solorzano JL, Perez-Gracia JL, Labiano S, Sanmamed MF, Azpilikueta A, Bolaños E, et al. Abscopal effects of radiotherapy are enhanced by combined immunostimulatory mAbs and are dependent on CD8 T cells and crosspriming. Cancer Res. 2016;76:5994–6005. doi:10.1158/0008-5472.CAN-16-0549. PMID:27550452
   PubMed Web of Science ®Google Scholar
• Cash H, Shah S, Moore E, Caruso A, Uppaluri R, Van Waes C, Allen C. mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer. Oncotarget. 2015;6:36400–17. PMID:26506415
   PubMed Web of Science ®Google Scholar
• Farsaci B, Higgins JP, Hodge JW. Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int J Cancer. 2012;130:1948–59. doi:10.1002/ijc.26219. PMID:21633954
   PubMed Web of Science ®Google Scholar
• Judd NP, Winkler AE, Murillo-Sauca O, Brotman JJ, Law JH, Lewis JS Jr, Dunn GP, Bui JD, Sunwoo JB, Uppaluri R. ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. Cancer Res. 2012;72:365–74. doi:10.1158/0008-5472.CAN-11-1831. PMID:22086849
   PubMed Web of Science ®Google Scholar
• Robbins PF, Kantor JA, Salgaller M, Hand PH, Fernsten PD, Schlom J. Transduction and expression of the human carcinoembryonic antigen gene in a murine colon carcinoma cell line. Cancer Res. 1991;51:3657–62. PMID:1712245
   PubMed Web of Science ®Google Scholar