PTENα functions as an immune suppressor and promotes immune resistance in PTEN-mutant cancer

作者：Yizhe Sun, Dan Lü, Yue Yin, Yue Yin, Jia Song, Yang Liu, Wenyan Hao, Fang Qi, Xin Zhang, Xin Zhang, Zhiqiang Lin, Zhiqiang Lin, Hui Liang, Xuyang Zhao, Yuxin Yin, Yuxin Yin, Yuxin Yin · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-25417-6 · 被引用次数：46 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Cytokine Signaling Pathways and Interactions、Inflammatory mediators and NSAID effects

Abstract PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. PTEN mutations have been implicated in immune regulation, however, the underlying mechanism is largely unknown. Here, we report that PTENα, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8 + T cell-mediated cytotoxicity, PTENα leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTENα-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTENα-inactive mutations. Furthermore, germline deletion of Ptenα in mice increases cell susceptibility to immune attack through augmenting stress granule formation and limiting synthesis of peroxidases, leading to massive oxidative cell death and severe inflammatory damage. We propose that PTENα protects tumor from T cell killing and thus PTENα is a potential target in antitumor immunotherapy.