中国科学技术大学魏海明研究小组发现，白细胞介素-34协调的肿瘤相关巨噬细胞重编程，是p53失活驱动肿瘤免疫逃逸所需的。2024年9月24日，《免疫》杂志在线发表了这项成果。

研究人员发现，癌症干细胞（CSC）建立了一个由白细胞介素-34（IL-34）协调的微环境，以促进p53失活肝癌的肿瘤发生。从机制上讲，研究人员发现Il34是一个被p53转录抑制的基因，p53丧失导致CSCs分泌IL-34。

IL-34诱导CD36介导的脂肪酸氧化代谢升高，从而驱动泡沫样肿瘤相关巨噬细胞（TAM）的M2样极化。这些IL-34协调的TAMs抑制了CD8⁺ T细胞介导的抗肿瘤免疫，从而促进了免疫逃逸。阻断IL-34-CD36通路引发抗肿瘤免疫，并与抗PD-1免疫疗法协同作用，导致完全反应。

该研究揭示了p53调节肿瘤免疫微环境的潜在机制，并为p53失活癌症的免疫治疗提供了潜在靶点。

据悉，作为癌症中最常见的基因突变，超过一半的人类癌症存在导致转录失活的p53突变。然而，p53如何调节免疫环境以创造免疫逃逸的微环境仍不清楚。

附：英文原文

Title: Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation

Author: Zhigang Nian, Yingchao Dou, Yiqing Shen, Jintang Liu, Xianghui Du, Yong Jiang, Yonggang Zhou, Binqing Fu, Rui Sun, Xiaohu Zheng, Zhigang Tian, Haiming Wei

Issue&Volume: 2024-09-24

Abstract: As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8+ T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.

DOI: 10.1016/j.immuni.2024.08.015

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00415-1