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Tp53 determines the spatial dynamics of M1/M2 tumor-associated macrophages and M1-driven tumoricidal effects

Yi-Jing Hsiao1,2, Min-Shu Hsieh3, Gee-Chen Chang4,5,6,7,8

  • 1Department of Clinical and Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.

Cell Death & Disease
|January 22, 2025
PubMed

Insights

Tumor-associated macrophages (TAMs) play a spatial role in lung cancer. Wild-type TP53 status influences M1/M2 TAM distribution and predicts better survival, especially with M1 macrophage dominance and immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • The spatial distribution and function of M1 and M2 tumor-associated macrophages (M1/M2 TAMs) in lung adenocarcinoma are not fully understood.
  • EGFR and TP53 are common mutations in lung adenocarcinoma, potentially influencing the tumor microenvironment.

Purpose of the Study:

  • To investigate the spatial characteristics and density of M1/M2 TAMs in relation to EGFR and TP53 mutation status in lung adenocarcinoma.
  • To elucidate the functional role of M1 TAMs in wild-type TP53 (wtp53) lung adenocarcinoma and their impact on patient survival and response to therapy.

Main Methods:

  • Next-generation sequencing and immunohistochemistry were used to analyze mutation status and M1/M2 TAM density in 117 lung adenocarcinomas.
  • In vitro studies examined the effect of M1 macrophage conditioned medium (M1 CM) on wtp53 lung cancer cells, including apoptosis induction and signaling pathway activation (JAK/STAT/p53).
  • In vivo experiments assessed the anti-tumor efficacy of M1 CM and polyinosinic:polycytidylic acid (poly I:C) in a p53-dependent manner.

Main Results:

  • Stromal M1 TAMs correlated with disease progression and smoking history.
  • Islet M1/M2 TAMs were prevalent in wtp53 tumors, with their distribution linked to wtp53 status.
  • Dominance of islet M1 TAMs and M1 signature were associated with improved survival in wtp53 lung adenocarcinoma patients.
  • M1 CM induced apoptosis in wtp53 cells via interferon-mediated JAK/STAT/p53 signaling, inhibiting tumorigenesis.
  • Higher M1 signature predicted better response to anti-PD1 therapy in wtp53 melanomas.

Conclusions:

  • TP53 status critically modulates the spatial distribution and anti-tumor activity of M1/M2 TAMs in lung adenocarcinoma.
  • The anti-tumor effects of M1 TAMs are dependent on p53 status, highlighting a mechanism involving interferon-JAK/STAT-p53 signaling.
  • p53 companion diagnostics could guide M1-oriented therapies, particularly for wtp53 patients, potentially enhancing immunotherapy efficacy.

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