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

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 PTEN alpha, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8(+) T cell-mediated cytotoxicity, PTEN alpha leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTEN alpha-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTEN alpha-inactive mutations. Furthermore, germline deletion of Pten alpha 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 PTEN alpha protects tumor from T cell killing and thus PTEN alpha is a potential target in antitumor immunotherapy. PTEN alpha is an N-terminally extended isoform of PTEN, a gene frequently mutated in human cancers. Here the authors show that PTEN alpha remains active in PTEN-mutant cancers and is associated with tumor immune escape by promoting tumor cell resistance to T cell cytotoxicity.