日本千叶癌症中心研究所Yosuke Togashi研究组，揭示了肿瘤微环境中线粒体转移介导免疫逃逸机制。相关论文于2025年1月22日在线发表于国际学术期刊《自然》。

研究人员分析了临床样本，并发现肿瘤浸润淋巴细胞（TIL）中的线粒体DNA（mtDNA）突变与癌细胞共享。此外，来自癌细胞的带有mtDNA突变的线粒体能够转移到TIL中。通常，TIL中的线粒体会通过活性氧进行线粒体自噬。然而，从癌细胞转移到TIL的线粒体不会经历线粒体自噬，研究人员发现这是由于有线粒体自噬抑制分子的存在。这些分子附着在线粒体上并与线粒体一起转移到TIL中，导致同源性替代。获得来自癌细胞的mtDNA突变的T细胞表现出代谢异常和衰老，伴随效应功能和记忆形成的缺陷。这反过来导致了体内外抗肿瘤免疫的损害。

因此，肿瘤组织中存在mtDNA突变是黑色素瘤或非小细胞肺癌患者在使用免疫检查点抑制剂时的预后不良因素。这些发现揭示了癌细胞通过线粒体转移实现免疫逃逸的新机制，并为未来癌症免疫治疗的开发提供了重要线索。

研究人员表示，肿瘤微环境中的癌细胞利用多种机制逃避免疫系统的攻击，特别是T细胞的攻击。例如，肿瘤微环境中的代谢重编程和TIL中的线粒体功能障碍会削弱抗肿瘤免疫反应。然而，这些过程的详细机制仍不清楚。

附：英文原文

Title: Immune evasion through mitochondrial transfer in the tumour microenvironment

Author: Ikeda, Hideki, Kawase, Katsushige, Nishi, Tatsuya, Watanabe, Tomofumi, Takenaga, Keizo, Inozume, Takashi, Ishino, Takamasa, Aki, Sho, Lin, Jason, Kawashima, Shusuke, Nagasaki, Joji, Ueda, Youki, Suzuki, Shinichiro, Makinoshima, Hideki, Itami, Makiko, Nakamura, Yuki, Tatsumi, Yasutoshi, Suenaga, Yusuke, Morinaga, Takao, Honobe-Tabuchi, Akiko, Ohnuma, Takehiro, Kawamura, Tatsuyoshi, Umeda, Yoshiyasu, Nakamura, Yasuhiro, Kiniwa, Yukiko, Ichihara, Eiki, Hayashi, Hidetoshi, Ikeda, Jun-ichiro, Hanazawa, Toyoyuki, Toyooka, Shinichi, Mano, Hiroyuki, Suzuki, Takuji, Osawa, Tsuyoshi, Kawazu, Masahito, Togashi, Yosuke

Issue&Volume: 2025-01-22

Abstract: Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly Tcell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2,3,4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. Tcells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.

DOI: 10.1038/s41586-024-08439-0

Source: https://www.nature.com/articles/s41586-024-08439-0