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Protein Kinase C Delta Regulates Mononuclear Phagocytes by Repressing Type I and II Interferon Signaling and Hinders Response to Immunotherapy in Cancer

ABSTRACT: Mononuclear phagocytes (MPs) comprise monocytes, macrophages and dendritic cells and play a crucial role in tissue homeostasis. However, accumulating evidence suggests that mononuclear phagocytes contribute to tumor progression and resistance to checkpoint blockade. Protein kinase C delta (PKCδ) is a serine/threonine kinase that plays a crucial role in regulating the immune response by preventing autoimmunity. However, the role of PKCδ in antitumor immunity is unknown. In this study, we found that PKCδ is abundantly expressed by MPs in several human and mouse tumors. PKCδ-/- mice were more resistant to growth of various cancers compared to wild-type mice and were more responsive to anti-PD-1 immunotherapy. Furthermore, we found that tumors from PKCδ-/- mice harbor a Th-1-skewed immune response including increased antigen cross-presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in wild-type mice, but not in PKCδ-/- mice. In addition, co-injection 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 wild-type M2-like macrophages co-injected with cancer cells. Finally, intrinsic loss of PKCδ functionally reprogrammed macrophages and dendritic cells by promoting their antigen presenting and cross-presenting capacity and triggered Type I and II interferon signaling. Our results suggest that PKCδ can be targeted to reprogram mononuclear phagocytes and augment checkpoint blockade efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE208394 | GEO | 2022/10/01

REPOSITORIES: GEO

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