scRNA-seq analysis of tumor infiltrating lymphocytes in PTENa-expressing tumors

As a tumor suppressor, PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. PTEN mutations have been implicated in immune regulation, but the underlying mechanism is largely unknown. We report that PTENa, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8+ T cell-mediated cytotoxicity, presence of PTENa leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTENa-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTENa-inactive mutations. Furthermore, germline deletion of Ptena 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 PTENa protects tumor from T cell killing and thus PTENa is a potential target in antitumor immunotherapy. Overall design: Study of tumor infiltration lymphocytes in Mock or PTENa expressing B16 Pten-/- tumors using 10x scRNA-seq technologies.