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

Yizhe Sun, Dan Lu (), Yue Yin, Jia Song, Yang Liu, Wenyan Hao, Fang Qi, Guangze Zhang, Xin Zhang, Liang Liu, Zhiqiang Lin, Hui Liang, Xuyang Zhao, Yan Jin and Yuxin Yin ()
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Yizhe Sun: Peking University Health Science Center
Dan Lu: Peking University Health Science Center
Yue Yin: Peking University Health Science Center
Jia Song: Peking University Health Science Center
Yang Liu: Peking University Health Science Center
Wenyan Hao: Peking University Health Science Center
Fang Qi: Peking University Health Science Center
Guangze Zhang: Peking University Health Science Center
Xin Zhang: Peking University Health Science Center
Liang Liu: Peking University Health Science Center
Zhiqiang Lin: Peking University Health Science Center
Hui Liang: Peking University Health Science Center
Xuyang Zhao: Peking University Health Science Center
Yan Jin: Peking University Health Science Center
Yuxin Yin: Peking University Health Science Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25417-6

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