Protein kinase C-eta is required for Treg-mediated suppression of anti-tumor and viral immunity

Abstract

Abstract We previously reported that protein kinase C-eta plays an important role in the contact-dependent suppressive activity of Tregs via its association with CTLA4, and that PKC-eta-deficient (Prkch−/−) Tregs fail to suppress anti-melanoma tumor immunity. Here we extend this study to a genetically engineered mouse model of HCC driven by CRISPR-Cas9-driven deletion of Pten and p53. In the Pten-p53 HCC model, Prkch Treg-specific conditional knockout (cKO) mice developed a lower tumor incidence, fewer tumors, lower degree of steatosis phenotype, and showed higher intratumoral CD4+ T cells than WT mice. In addition, B cells and resident DCs displayed higher levels of the costimulatory ligand CD86 in dLNs of cKO mice. Increased CD4+ T cells, memory T lymphocytes, and cytokines production were observed in spleen of cKO mice. These results indicate that Treg-expressed PKC-eta is required for Treg-mediated suppression of anti-HCC tumor immunity. To further explore the importance of PKC-eta in Teff cells, the LCMVArm acute infection model, as well as the in vitro activation of murine or human CD8+ T cells were used. We found that purified Prkch−/− mouse CD8+ T cells as well as PRKCH knockdown human CD8+ T cells displayed intact T cell activation in vitro as measured by proliferation and expression of GzmB and IFNg. Interestingly, Treg-specific cKO mice showed improved viral clearance and displayed enhanced expression of GzmB and IFNg by virus-specific CD8+ T cells. Thus, global PKC-eta deletion does not impair overall CD8+ T cell-mediated immunity implying that selective pharmacological PKC-eta inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor- and viral-specific immunity.