Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number107643
JournalCell Reports
Volume31
Issue number6
DOIs
StatePublished - 12 May 2020

Keywords

  • immunotherapy
  • molecular target
  • protein kinase A catalytic subunit
  • tumor microenvironment
  • tumor-associated macrophage

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  • Cite this

    Na, Y. R., Kwon, J. W., Kim, D. Y., Chung, H., Song, J., Jung, D., Quan, H., Kim, D., Kim, J. S., Ju, Y. W., Han, W., Ryu, H. S., Lee, Y. S., Hong, J. J., & Seok, S. H. (2020). Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages. Cell Reports, 31(6), [107643]. https://doi.org/10.1016/j.celrep.2020.107643