Abstract PL1: Potential of Radiation Therapy to Convert the Tumor Into an In Situ Vaccine

Abstract

Abstract Radiotherapy (RT) has revealed an ideal adjuvant to cancer immunotherapy, because of it's ability to convert the irradiated tumor into an individualized, in situ vaccine. 1 DNA damage response (DDR) contributes to immune rejection of tumors, a mechanism at least in part responsible of the success of platinum and RT combinations. 2 RT-induced cell death can evoke T cell memory, inducing effects outside the irradiated field, defined as abscopal. In the setting of metastatic cancer, however, the occurrence of abscopal effects is extremely rare, 3 because of the established immune-suppressive microenvironment. 4 Thus, the pro-immunogenic effects of radiotherapy is best exploited in combination with immunotherapy, 5,6 and combination of RT and immune checkpoint blockade (ICB) has matured to reach clinical translation. 7 8 The issue of RT dose and fractionation is particularly relevant to abscopal responses. 8,9 A mechanism underlying this dose-dependence was recently elucidated. 10 In mice bearing bilateral TSA murine breast carcinoma a single dose of 20 or 30Gy combined with ICB achieved comparable in field control to that of a regimen of 8GyX3 fractions, but only the fractionated regimen induced abscopal responses. An interferon type I (IFN-I) gene signature was associated with the 8GyX3 fractions but not with a single dose of 20 or 30 Gy. IFN-I plays a key role in cross priming and rejection of cancer. 11 RT-generates double strands (ds) DNA fragments reach the cytoplasm of irradiated cells where they are “sensed” by cGAS/STING (cGAS=cyclic GMP-AMP synthase and its adaptor protein STING= stimulator of interferon genes, aka transmembrane protein 173 – TMEM173). cGAS binds cytosolic dsDNA to initiate IFN-I responses upon STING stimulation, resulting in dendritic cell recruitment and cross-priming of effector T-cells, key steps to convert the tumor into an in situ vaccine. In multiple carcinoma murine and human carcinoma cells as the radiation dose increased, cytosolic dsDNA was found to accumulate to a threshold above which induction of three prime repair exonuclease 1 (Trex1) occured, an enzyme that degrades cytoplasmic DNA. Single doses in excess of 10-12 Gy induced Trex1, with rapid degradation of cytosolic dsDNA, and abrogation of IFN induction, impairing RT-induced abscopal effects. These findings support the choice of 3-5 doses of 8 Gy each, when radiotherapy is combined with immunotherapy. Interestingly, a recent dose escalation clinical trial demonstrated an inferior incidence of pathological response (pCR) when breast cancers were irradiated beyond a certain threshold: pCR was 67% in the cohort treated with 8.5 Gy X3 and decreased to 43 and 33% after three fractions of 9.5Gy and 10.5 Gy, respectively. 12 Ongoing investigations are defining optimal sequencing and treatment fields. 1. OncoImmunology 2014; 3: e28518. 2. Oncoimmunology 2017; 6(3): e1274479. 3. Curr Probl Cancer 2016; 40: 25-37. 4. Annu Rev Immunol 2011; 29: 235-71. 5. Int J Radiat Oncol Biol Phys 2004; 58: 862-70. 6. Lancet Oncol 2015; 16(7): 795-803. 7. Clin Cancer Res 2005; 11: 728-34. 8. J Immunother Cancer 2016; 4: 51. 9. Clin Cancer Res 2009; 15(17): 5379-88. 10. Nat Commun 2017; 8: 15618. 11.Trends Immunol 2013; 34(2): 67-73. 12. Int J Radiat Oncol Biol Phys 2013; 85(5): 1193-9. Citation Format: Formenti SC. Potential of Radiation Therapy to Convert the Tumor Into an In Situ Vaccine [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PL1.