Immune evasion through mitochondrial transfer in the tumour microenvironment

• 成果类型: Article
• 署名作者: 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
• 署名单位: Chiba Cancer Center; Chiba University; Chiba University; Okayama University; Okayama University; Okayama University; Chiba Cancer Center; Chiba University; University of Yamanashi; Chiba University; University of Tokyo; University of Tokyo; Kindai University (Kinki University); National Cancer Center - Japan; Chiba Cancer Center; Chiba Cancer Center; Chiba Cancer Center; Kumamoto University; Saitama Medical University; Shinshu University; Chiba University; Okayama University; National Cancer Center - Japan; Chiba University; University of Tokyo; Kindai University (Kinki University)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3447
• DOI: 10.1038/s41586-024-08439-0
• 发表日期: 2025-02-06
• 关键词: cd8(+) t-cells; cancer-cells; respiratory capacity; mutations; genome; ros; expression; autophagy; DYNAMICS; antibody

摘要

Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell 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. T cells 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.