Prevalence of intratumoral regulatory T cells expressing neuropilin-1 is associated with poorer outcomes in patients with cancer.

Despite the success of immune checkpoint blockade therapy, few strategies sufficiently overcome immunosuppression within the tumor microenvironment (TME). Targeting regulatory T cells (T) is challenging, because perturbing intratumoral T function must be specific enough to avoid systemic inflammatory side effects. Thus, no T-targeted agents have proven both safe and efficacious in patients with cancer. Neuropilin-1 (NRP1) is recognized for its role in supporting intratumoral T function while being dispensable for peripheral homeostasis. Nonetheless, little is known about the biology of human NRP1 T and the signals that regulate NRP1 expression. Here, we report that NRP1 is preferentially expressed on intratumoral T across six distinct cancer types compared to healthy donor peripheral blood [peripheral blood lymphocyte (PBL)] and site-matched, noncancer tissue. Furthermore, NRP1 T prevalence is associated with reduced progression-free survival in head and neck cancer. Human NRP1 T have broad activation programs and elevated suppressive function. Unlike mouse T, we demonstrate that NRP1 identifies a transient activation state of human T driven by continuous T cell receptor (TCR) signaling through the mitogen-activated protein kinase pathway and interleukin-2 exposure. The prevalence of NRP1 T in patient PBL correlates with the intratumoral abundance of NRP1 T and may indicate higher disease burden. These findings support further clinical evaluation of NRP1 as a suitable therapeutic target to enhance antitumor immunity by inhibiting T function in the TME.