Combination therapy with radiation and PARP inhibition enhances responsiveness to anti-PD-1 therapy in colorectal tumor models

Abstract Purpose The majority of colorectal cancers are resistant to cancer immune-checkpoint inhibitors. Ionizing radiation (IR) and several radiosensitizers, including PARP inhibitors, can enhance responsiveness to immune checkpoint inhibitors by potentially complementary mechanisms of action. We assessed the ability of radiation and PARP-inhibition to induce pro-immunogenic changes in tumor cells and enhance their in vivo responsiveness to anti-PD-1 antibodies. Materials and Methods We performed a candidate drug screen and utilized flow cytometry to assess effects of the PARP inhibitor, veliparib, on IR-mediated changes in MHC-1 antigen presentation and surface localization of immune-modulating proteins including PD-L1 and calreticulin in colorectal cancer tumor models. RT-PCR was used to assess the effects of veliparib and radiation on the expression of proinflammatory and immunosuppressive cytokines. The ability of concurrent PARP inhibition and subablative doses of radiotherapy to enhance in vivo responsiveness to anti-PD-1 antibodies was assessed using unilateral flank-tumor models +/- T-cell depletion. Results Veliparib was a potent radiosensitizer in both cell lines. Radiation increased surface localization of MHC-1 and PD-L1 in a dose-dependent manner and veliparib pretreatment significantly enhanced these effects with high (8 Gy) but not lower radiation doses. Enhancement of MHC-1 and PD-L1 surface localization by IR and IR + veliparib remained significant 1, 3, and 7 days after treatment. IR significantly increased delayed tumoral expression of pro-inflammatory cytokines INF-Ƴ and CXCL10 but had no significant effect on the expression of IL-6 or TGF-β. Concurrent administration of veliparib and subablative radiotherapy (8 Gy x 2) significantly prolonged anti-PD-1 mediated in vivo tumor growth delay and survival in both tumor models. Moreover, these effects were more pronounced in the microsatellite instability-mutated MC38 tumor model. Enhancement of anti-PD-1 mediated tumor growth delay with veliparib and IR was attenuated by CD8+ T-cell depletion. Conclusions We provide preclinical evidence for a novel therapeutic strategy to enhance responsiveness of colorectal tumors to immune checkpoint inhibitors.