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

Abstract

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.

Biopterin metabolism and nitric oxide recoupling in cancer

“…Highlighting the direct antagonistic effect of NOS uncoupling on T cell activity, de Sanctis et al found that inhibiting ARG1 and NOS2 expression inhibited accumulation of nitro-Tyrosine moieties in T cells and sensitized pancreatic tumor models to attack by TERT specific CAR-T (33). In addition to modulating the negative effects of NOS uncoupling, restoring native NO production and downstream signaling by activated T cells has also been proposed as an attractive therapeutic strategy (87).…”