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Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by

Zhigang Nian1, Yingchao Dou2, Yiqing Shen2

  • 1Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institue of Immunology, University of Science and Technology of China, Hefei, Anhui 230027, China.

Immunity
|September 25, 2024
PubMed

Insights

p53 mutations in cancer promote immune escape by enabling cancer stem cells to secrete interleukin-34 (IL-34). This IL-34 drives tumor-associated macrophages that suppress T cell immunity, but blocking this pathway enhances antitumor responses.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • TP53 mutations are common in human cancers, leading to transcriptional inactivation.
  • The role of p53 in shaping the tumor immune microenvironment and facilitating immune escape is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which p53 inactivation influences the tumor immune landscape.
  • To identify novel therapeutic targets for p53-mutated cancers.

Main Methods:

  • Investigated the role of interleukin-34 (IL-34) in liver cancer with p53 inactivation.
  • Analyzed the interaction between IL-34, CD36, tumor-associated macrophages (TAMs), and CD8+ T cells.
  • Evaluated the therapeutic potential of blocking the IL-34-CD36 axis in combination with anti-PD-1 immunotherapy.

Main Results:

  • Loss of p53 in liver cancer stem cells (CSCs) leads to transcriptional upregulation and secretion of IL-34.
  • IL-34 promotes M2-like polarization of foam-like TAMs via CD36-mediated fatty acid metabolism.
  • These TAMs suppress CD8+ T cell-mediated antitumor immunity, promoting immune escape.
  • Blocking the IL-34-CD36 axis restores antitumor immunity and synergizes with anti-PD-1 therapy, achieving complete response.

Conclusions:

  • p53 inactivation creates an immune-suppressive niche via the IL-34-orchestrated CSC-TAM axis.
  • Targeting the IL-34-CD36 pathway represents a promising strategy for immunotherapy in p53-mutated cancers.
Keywords:
CD36IL-34cancer stem cellfoam-like macrophageimmune checkpoint inhibitorliver cancerp53tumor immune escapetumor immune microenvironmenttumor-associated macrophage

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