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

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

doi:10.1126/SCIADV.ADD3231

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

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

Cellular Biology and Anatomy

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	eadd3231
Journal	Science Advances
Volume	9
Issue number	51
DOIs	https://doi.org/10.1126/SCIADV.ADD3231
State	Published - Dec 2023

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Chaib, M., Holt, J. R., Fisher, E. L., Sipe, L. M., Bohm, M. S., Joseph, S. C., Simmons, B. W., Simon, S. E., Yarbro, J. R., Tanveer, U., Halle, J. L., Carson, J. A., Hollingsworth, T. J., Wei, Q. Q., Rathmell, J. C., Thomas, P. G., Hayes, D. N., & Makowski, L. (2023). Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer. Science Advances, 9(51), Article eadd3231. https://doi.org/10.1126/SCIADV.ADD3231

Chaib, M, Holt, JR, Fisher, EL, Sipe, LM, Bohm, MS, Joseph, SC, Simmons, BW, Simon, SE, Yarbro, JR, Tanveer, U, Halle, JL, Carson, JA, Hollingsworth, TJ, Wei, QQ, Rathmell, JC, Thomas, PG, Hayes, DN & Makowski, L 2023, 'Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer', Science Advances, vol. 9, no. 51, eadd3231. https://doi.org/10.1126/SCIADV.ADD3231

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title = "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 TH1-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.",

author = "Mehdi Chaib and Holt, {Jeremiah R.} and Fisher, {Emilie L.} and Sipe, {Laura M.} and Bohm, {Margaret S.} and Joseph, {Sydney C.} and Simmons, {Boston W.} and Simon, {Samson Eugin} and Yarbro, {Johnathan R.} and Ubaid Tanveer and Halle, {Jessica L.} and Carson, {James A.} and Hollingsworth, {T. J.} and Wei, {Qing Qing} and Rathmell, {Jeffrey C.} and Thomas, {Paul G.} and Hayes, {D. Neil} and Liza Makowski",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = dec,

doi = "10.1126/SCIADV.ADD3231",

language = "English (US)",

volume = "9",

journal = "Science Advances",

issn = "2375-2548",

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T1 - Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer

AU - Chaib, Mehdi

AU - Holt, Jeremiah R.

AU - Fisher, Emilie L.

AU - Sipe, Laura M.

AU - Bohm, Margaret S.

AU - Joseph, Sydney C.

AU - Simmons, Boston W.

AU - Simon, Samson Eugin

AU - Yarbro, Johnathan R.

AU - Tanveer, Ubaid

AU - Halle, Jessica L.

AU - Carson, James A.

AU - Hollingsworth, T. J.

AU - Wei, Qing Qing

AU - Rathmell, Jeffrey C.

AU - Thomas, Paul G.

AU - Hayes, D. Neil

AU - Makowski, Liza

PY - 2023/12

Y1 - 2023/12

N2 - 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 TH1-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.

AB - 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 TH1-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.

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

Abstract

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