Leveraging the Treg-intrinsic CTLA4-PKCη signaling pathway for cancer immunotherapy

Abstract Our previous studies revealed a critical role of a novel CTLA4-PKCη signaling in mediating the suppressive activity of Tregs in antitumor immunity. Here, we extended these findings into a biologically and clinically more relevant context. We have analyzed the role of PKCη in antitumor immunity in intact tumor-bearing mice with Treg− or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. Using two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16-F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive tumor microenvironment, indicated by increased numbers and function of tumor-infiltrating CD8+ T cells and elevated expression of the costimulatory ligand CD86 on CD103+ DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth and the abundance or functionality of CD8+ T cells. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Flt3L-expressing B16-F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies. These findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat cancer patients, especially when combined with adjuvant therapies. Funded by the NIH grant 5R01CA233862