Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Nitric oxide (NO) is a signaling molecule produced by NO synthases (NOS1–3) to control processes such as neurotransmission, vascular permeability, and immune function. Although myeloid cell–derived NO has been shown to suppress T-cell responses, the role of NO synthesis in T cells themselves is not well understood. Here, we showed that significant amounts of NO were synthesized in human and murine CD8(+) T cells following activation. Tumor growth was significantly accelerated in a T cell–specific, Nos2-null mouse model. Genetic deletion of Nos2 expression in murine T cells altered effector differentiation, reduced tumor infiltration, and inhibited recall responses and adoptive cell transfer function. These data show that endogenous NO production plays a critical role in T cell–mediated tumor immunity.