| First Author | Na YR | Year | 2020 |
| Journal | Cell Rep | Volume | 31 |
| Issue | 6 | Pages | 107643 |
| PubMed ID | 32402274 | Mgi Jnum | J:300333 |
| Mgi Id | MGI:6489046 | Doi | 10.1016/j.celrep.2020.107643 |
| Citation | Na YR, et al. (2020) Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages. Cell Rep 31(6):107643 |
| abstractText | 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 alphaCTLA-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. |
