Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer
Mehdi Chaib, Jeremiah Holt, Emilie L. Fisher, Laura M. Sipe, Margaret S. Bohm, S Joseph, Boston W. Simmons, Samson Eugin Simon, Johnathan R. Yarbro, Ubaid Tanveer, Jessica L. Halle, James A. Carson, TJ Hollingsworth, Qingqing Wei, Jeffrey C. Rathmell, Paul G. Thomas, D. Neil Hayes, Liza Makowski
Abstract
Mononuclear phagocytes (MPs) play a crucial role in tissue homeostasis; however, MPs also contribute to tumor progression and resistance to immune checkpoint blockade (ICB). Targeting MPs could be an effective strategy to enhance ICB efficacy. We report that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors. PKCδ −/− mice displayed reduced tumor progression compared to wild types, with increased response to anti–PD-1. Tumors from PKCδ −/− mice demonstrated T H 1-skewed immune response including increased antigen presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in control but not PKCδ −/− mice. Coinjection of PKCδ −/− M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to PKCδ +/+ controls. PKCδ deficiency reprogrammed MPs by activating type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram MPs to augment ICB efficacy.