Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1

摘要

T cells play a critical role in tumor immunosurveillance by eliminating newly transformed somatic cells. However; tumor cell variants can escape from immunological control after immunoediting; leading to tumor progression. Whether and how t cells respond to tumor growth remain unclear. Here; we found that tumor-infiltrating t cells exhibited persistently up-regulated expression of the activator protein 1 (ap-1) subunit c-fos during tumor progression. The ectopic expression of c-fos in t cells exacerbated tumor growth; whereas the t-cell-specific deletion of c-fos reduced tumor malignancy. This unexpected immunosuppressive effect of c-fos was mediated through the induced expression of immune inhibitory receptor programmed death 1 (pd-1) via the direct binding of c-fos to the ap-1-binding site in the pdcd1 (gene encoding pd-1) promoter. A knock-in mutation of this binding site abrogated pd-1 induction; augmented antitumor t-cell function and repressed tumor growth. Taken together; these findings indicate that t-cell c-fos subsequently induces pd-1 expression in response to tumor progression and that disrupting such induction is essential for repression of tumor growth.