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.
Highlights
PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis
Researches on tumor immune escape still mainly focus on the effects of tumor cells on T cells, while little is known about whether tumor cells can escape from cytotoxic T lymphocytes (CTLs)-mediated killing through modulating their own metabolic state
Utilizing gene set enrichment analysis (GSEA), we found that genes related to adaptive immune response were selectively enriched in cancers with phosphatase-inactive mutations as compared with those with stop-gained mutations (Fig. 1c)
Summary
PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. Previous studies have revealed that tumor cells can hijack strategies developed to limit immune responses, thereby affecting priming, activation, and recruitment of T cells, causing tumor immune escape[9] Apart from these processes of T cells, effective anti-tumor immunity requires cytotoxic T lymphocytes (CTLs)-mediated cell killing[10]. Researches have shown that the function of CTLs depends on the ROS production in the target cells, and recent studies further uncover that CTLs cause different types of cell death depending on the context of the target cells[11,12,13] These phenomena lead to the hypothesis that, instead of affecting T cell function, tumor-intrinsic factors may directly affect the susceptibility of tumor cells to CTLs. To date, researches on tumor immune escape still mainly focus on the effects of tumor cells on T cells, while little is known about whether tumor cells can escape from CTLs-mediated killing through modulating their own metabolic state. Our data demonstrate that PTENα acts as a suppressor of T cell cytotoxicity-induced oxidative cell death, and highlight the importance of targeting PTENα in antitumor immune therapy
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