DNMTi plus anti-4-1BB therapy reverses suppressive tumor microenvironment and reduces tumor burden in ovarian cancer

Abstract

Abstract Novel therapies are urgently needed for ovarian cancer (OC), the fifth deadliest cancer in women. Better OC prognosis is associated with high tumor-infiltrating CD8 T cells, but OC is generally characterized by an immunosuppressive tumor microenvironment (TME), with less than 10% of patients responding to immune checkpoint blockade therapy in clinical trials. DNA methyltransferase inhibitors (DNMTi) activate transcription of repetitive elements to induce a type I interferon response in OC, which recruits and activates host immune cells to fight the tumor. Additionally, changes in DNA methylation in T cells regulate T cell memory. Thus, DNMTi increase anti-tumor immunity through 1) tumor IFN response and 2) reversal of T cell exhaustion. To test the hypothesis that combination epigenetic and immune therapy could increase the anti-tumor response in OC, we treated an immunocompetent mouse model of OC with DNMTi +/− anti-CD137. The ID8 MOSE P53−/− model grows intraperitoneally and produces ascites, mimicking human OC which is 90% P53 mutant. The TME of this model is immunosuppressive and it is not responsive to immune checkpoint blockade therapy. At 9 weeks post tumor injection, we observed the following survival percentages: 50% for the combination group, 30% for the DNMTi group, and 0% survival for the both the anti-CD137 and mock groups. We also observed statistically significant increases in %CD3+IFNg+ T cells in the spleen for the DNMTi + anti-CD137 group compared to the mock group. We hypothesize that anti-CD137 treatment is activating immune cells recruited by DNMTi. Future experiments will manipulate cytokine expression to delineate mechanism. We thus describe a novel immunotherapeutic combination for ovarian cancer.