Protein kinase A catalytic subunit is a molecular switch that promotes the pro-tumoral function of macrophages

Cited 15 time in scopus
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Title
Protein kinase A catalytic subunit is a molecular switch that promotes the pro-tumoral function of macrophages
Author(s)
Y R Na; J W Kwon; D Y Kim; H Chung; J Song; D Jung; H Quan; Daesik Kim; J S Kim; Y W Ju; W Han; H S Ryu; Y S Lee; Jung Joo Hong; S H Seok
Bibliographic Citation
Cell Reports, vol. 31, no. 6, pp. 107643-107643
Publication Year
2020
Abstract
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.
Keyword
immunotherapymolecular targetprotein kinase A catalytic subunittumor microenvironmenttumor-associated macrophage
ISSN
2211-1247
Publisher
Elsevier-Cell Press
DOI
http://dx.doi.org/10.1016/j.celrep.2020.107643
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > National Primate Research Center > 1. Journal Articles
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