Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages
Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages
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DOI：
10.1016/j.celrep.2020.107643
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发表时间：
2020-05-12
期刊：
影响因子：
8.8
通讯作者：
Seok, Seung Hyeok
中科院分区：
文献类型：
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作者：
Na, Yi Rang;Kwon, Jung Won;Seok, Seung Hyeok
由于目前的治疗仅使少数癌症患者受益，因此需要额外的治疗靶点。肿瘤相关巨噬细胞（TAM）已引起人们的注意，以改善治疗反应，但监管策略仍然难以捉摸。在这里，我们表明，蛋白激酶A催化亚基（PKA-C）作为一个分子开关，诱导肿瘤内的促肿瘤免疫抑制巨噬细胞表型。在人类和小鼠乳腺癌中，TAM中过度活化的PKA通过诱导血管内皮生长因子A（VEGFA）、白细胞介素-10（IL-10）和巨噬细胞源性β-内酰胺酶1（ARG 1）表达，为癌症进展创造了有害的微环境。PKA-C基因缺失的巨噬细胞倾向于促炎，提示可能的免疫靶点。脂质体PKA抑制剂的递送促进小鼠中的肿瘤消退并消除促肿瘤TAM功能。当与α CTLA-4抗体组合时，靶向PKA的治疗效果是显著的，使分化簇8（CD 8）（+）GranzymeB（+）T细胞增加约60倍。我们的研究结果证明了TAM PKA-C在肿瘤进展中的关键作用，并表明靶向PKA-C有效地增强了癌症治疗反应。
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 alpha CTLA-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.