Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer. Academic Article uri icon

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 (PKC), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors. PKC-/- mice displayed reduced tumor progression compared to wild types, with increased response to anti-PD-1. Tumors from PKC-/- mice demonstrated TH1-skewed immune response including increased antigen presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in control but not PKC-/- mice. Coinjection of PKC-/- M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to PKC+/+ controls. PKC deficiency reprogrammed MPs by activating type I and type II interferon signaling. Thus, PKC might be targeted to reprogram MPs to augment ICB efficacy.

published proceedings

  • Sci Adv

author list (cited authors)

  • Chaib, M., Holt, J. R., Fisher, E. L., Sipe, L. M., Bohm, M. S., Joseph, S. C., ... Makowski, L.

complete list of authors

  • Chaib, Mehdi||Holt, Jeremiah R||Fisher, Emilie L||Sipe, Laura M||Bohm, Margaret S||Joseph, Sydney C||Simmons, Boston W||Eugin Simon, Samson||Yarbro, Johnathan R||Tanveer, Ubaid||Halle, Jessica L||Carson, James A||Hollingsworth, TJ||Wei, QingQing||Rathmell, Jeffrey C||Thomas, Paul G||Hayes, D Neil||Makowski, Liza