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

Yi Rang Na1, Jung Won Kwon1, Da Young Kim1

  • 1Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.

Cell Reports
|May 14, 2020
PubMed

Insights

Targeting protein kinase A catalytic subunit (PKA-C) in tumor-associated macrophages (TAMs) can reprogram them to fight cancer. Inhibiting PKA-C promotes anti-tumor immunity and enhances cancer therapy responses.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Current cancer therapies are effective for a limited number of patients, necessitating novel therapeutic targets.
  • Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment, but strategies to modulate their function are needed.

Purpose of the Study:

  • To investigate the role of protein kinase A catalytic subunit (PKA-C) in regulating TAM phenotype and function.
  • To evaluate PKA-C as a potential therapeutic target for cancer treatment.

Main Methods:

  • Analysis of PKA-C expression in human and murine breast cancer TAMs.
  • Genetic deletion of PKA-C in macrophages.
  • In vivo studies using liposomal PKA inhibitor and combination therapy with αCTLA-4 antibody in mouse models.
  • Assessment of macrophage phenotype, cytokine expression (VEGFA, IL-10, ARG1), and anti-tumor immune cell infiltration (CD8+ T cells).

Main Results:

  • Overactivated PKA-C in TAMs promotes a pro-tumoral, immunosuppressive phenotype by upregulating VEGFA, IL-10, and ARG1.
  • Genetic deletion of PKA-C shifts macrophages towards a pro-inflammatory state.
  • Liposomal PKA inhibitor treatment led to tumor regression and abrogated pro-tumoral TAM functions in mice.
  • Combination therapy with PKA inhibitor and αCTLA-4 antibody significantly increased CD8+ GranzymeB+ T cells, enhancing anti-tumor immunity.

Conclusions:

  • PKA-C acts as a crucial molecular switch controlling TAM immunosuppressive functions.
  • Targeting PKA-C in TAMs represents a promising immunotherapeutic strategy to augment cancer treatment efficacy.
  • Combined targeting of PKA-C and immune checkpoints like CTLA-4 shows potent anti-tumor activity.
Keywords:
immunotherapymolecular targetprotein kinase A catalytic subunittumor microenvironmenttumor-associated macrophage

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