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Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.

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_H1-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.

SUBMITTER: Chaib M

PROVIDER: S-EPMC10745701 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.

Chaib Mehdi M Holt Jeremiah R JR Fisher Emilie L EL Sipe Laura M LM Bohm Margaret S MS Joseph Sydney C SC Simmons Boston W BW Eugin Simon Samson S Yarbro Johnathan R JR Tanveer Ubaid U Halle Jessica L JL Carson James A JA Hollingsworth T J TJ Wei QingQing Q Rathmell Jeffrey C JC Thomas Paul G PG Hayes D Neil DN Makowski Liza L

Science advances 20231222 51

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<sup>-/-</sup> mice displayed reduced tumor progression compared to wild types, with increased response to anti-PD-1. Tum ...[more]

PMID: 38134280

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Project description:BackgroundHypoxia is a hallmark of the tumor microenvironment (TME) and in addition to altering metabolism in cancer cells, it transforms tumor-associated stromal cells. Within the tumor stromal cell compartment, tumor-associated macrophages (TAMs) provide potent pro-tumoral support. However, TAMs can also be harnessed to destroy tumor cells by monoclonal antibody (mAb) immunotherapy, through antibody dependent cellular phagocytosis (ADCP). This is mediated via antibody-binding activating Fc gamma receptors (FcγR) and impaired by the single inhibitory FcγR, FcγRIIb.MethodsWe applied a multi-OMIC approach coupled with in vitro functional assays and murine tumor models to assess the effects of hypoxia inducible factor (HIF) activation on mAb mediated depletion of human and murine cancer cells. For mechanistic assessments, siRNA-mediated gene silencing, Western blotting and chromatin immune precipitation were utilized to assess the impact of identified regulators on FCGR2B gene transcription.ResultsWe report that TAMs are FcγRIIbbright relative to healthy tissue counterparts and under hypoxic conditions, mononuclear phagocytes markedly upregulate FcγRIIb. This enhanced FcγRIIb expression is transcriptionally driven through HIFs and Activator protein 1 (AP-1). Importantly, this phenotype reduces the ability of macrophages to eliminate anti-CD20 monoclonal antibody (mAb) opsonized human chronic lymphocytic leukemia cells in vitro and EL4 lymphoma cells in vivo in human FcγRIIb+/+ transgenic mice. Furthermore, post-HIF activation, mAb mediated blockade of FcγRIIb can partially restore phagocytic function in human monocytes.ConclusionOur findings provide a detailed molecular and cellular basis for hypoxia driven resistance to antitumor mAb immunotherapy, unveiling a hitherto unexplored aspect of the TME. These findings provide a mechanistic rationale for the modulation of FcγRIIb expression or its blockade as a promising strategy to enhance approved and novel mAb immunotherapies.

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Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.

Publications

Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.

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