Using transplantable and genetically engineered autochthonous tumor models, Liu et al. showed that protein kinase C-eta (PKCη) mediated the immunosuppressive function of Tregs. PKCη deletion in Tregs, but not in CD8+ T cells, reduced tumor growth, increased tumor-infiltrating activated (GzmB+, IFNγ+, and TNFα+) and memory (CD44+) CD8+ T cells, and increased expression of the costimulatory ligand CD86 on intratumoral DCs. Combination of irradiated Flt3L-expressing B16F10 tumor cell vaccination and Treg-specific PKCη deletion post-tumor implantation displayed a pronounced reduction in tumor growth compared to monotherapy.
Contributed by Shishir Pant
Background: Our previous studies revealed a critical role of a novel CTLA4-protein kinase C-eta (PKCη) signaling axis in mediating the suppressive activity of regulatory T cells (Tregs) in antitumor immunity. These studies have employed adoptive transfer of germline PKCη-deficient (Prkch -/-) Tregs into Prkch +/+ mice prior to tumor implantation. Here, we extended these findings into a biologically and clinically more relevant context.
Methods: We have analyzed the role of PKCη in antitumor immunity and the tumor microenvironment (TME) in intact tumor-bearing mice with Treg-specific or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. In addition to measuring tumor growth, we analyzed the phenotype and functional attributes of tumor-infiltrating immune cells, particularly Tregs and dendritic cells (DCs).
Results: Using two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found, first, 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 TME, indicated by increased numbers and function of tumor-infiltrating CD8+ effector T cells and elevated expression of the costimulatory ligand CD86 on intratumoral DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth or the abundance and functionality of CD8+ effector T cells, consistent with findings that Prkch -/- CD8+ T cells proliferated normally in response to in vitro polyclonal or specific antigen stimulation. 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 Fms-like tyrosine kinase 3 ligand (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.
Conclusion: These findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat patients with cancer, especially when combined with adjuvant therapies.
Author Info: (1) La Jolla Institute for Immunology, La Jolla, California, USA hliu@lji.org. (2) La Jolla Institute for Immunology, La Jolla, California, USA. CERTIS, San Diego, California, USA.
Author Info: (1) La Jolla Institute for Immunology, La Jolla, California, USA hliu@lji.org. (2) La Jolla Institute for Immunology, La Jolla, California, USA. CERTIS, San Diego, California, USA. (3) La Jolla Institute for Immunology, La Jolla, California, USA. (4) La Jolla Institute for Immunology, La Jolla, California, USA. (5) University of Massachusetts Medical School, Worcester, Massachusetts, USA. (6) La Jolla Institute for Immunology, La Jolla, California, USA.
