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Kim, Dae Sik
유전체 교정 연구단
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Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages

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Title
Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages
Author(s)
Yi Rang Na; Jung Won Kwon; Da Young Kim; Hyewon Chung; Juha Song; Daun Jung; Hailian Quan; Daesik Kim; Jin-Soo Kim; Young Wook Ju; Wonshik Han; Han Suk Ryu; Yun-Sang Lee; Jung Joo Hong; Seung Hyeok Seok
Subject
immunotherapy, ; molecular target, ; protein kinase A catalytic subunit, ; tumor microenvironment, ; tumor-associated macrophage
Publication Date
2020-05
Journal
CELL REPORTS, v.31, no.6, pp.107643
Publisher
CELL PRESS
Abstract
© 2020 The Author(s). As current therapies benefit only a minority of cancer patients, additional therapeutic targets are needed. Tumor-associated macrophages (TAMs) have attracted attention for improving therapeutic responses, yet regulatory strategies remain elusive. Here, we show that the protein kinase A catalytic subunit (PKA-C) acts as a molecular switch, inducing a pro-tumoral immunosuppressive macrophage phenotype within tumors. In human and murine breast cancer, overactivated PKA in TAMs creates a detrimental microenvironment for cancer progression by inducing vascular endothelial growth factor A (VEGFA), interleukin-10 (IL-10), and macrophage-derived arginase 1 (ARG1) expression. Macrophages with genetic deletion of PKA-C are prone to be pro-inflammatory, suggesting a possible immunotherapeutic target. Delivery of liposomal PKA inhibitor facilitates tumor regression and abrogates pro-tumoral TAM functions in mice. The therapeutic effect of targeting PKA is pronounced when combined with αCTLA-4 antibody, increasing cluster of differentiation 8 (CD8)+GranzymeB+ T cells by about 60-fold. Our findings demonstrate critical roles of TAM PKA-C in tumor progression and suggest that targeting PKA-C efficiently augments cancer treatment responses. © 2020 The Author(s)Na et al. show that overactivated protein kinase A catalytic subunit beta (PKA-Cβ) of macrophages creates a detrimental microenvironment for the breast cancer progression. Delivery of a liposomal PKA inhibitor reduces pro-tumoral function of macrophages and induces the activation of cytotoxic T lymphocytes, leading to a tumor regression
URI
https://pr.ibs.re.kr/handle/8788114/8621
DOI
10.1016/j.celrep.2020.107643
ISSN
2211-1247
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > 1. Journal Papers (저널논문)
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