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-regs) is challenging, because perturbing intratumoral T-reg function must be specific enough to avoid systemic inflammatory side effects. Thus, no T-reg-targeted agents have proven both safe and efficacious in patients with cancer. Neuropilin-1 (NRP1) is recognized for its role in supporting intratumoral T-reg function while being dispensable for peripheral homeostasis. Nonetheless, little is known about the biology of human NRP1(+) T-regs and the signals that regulate NRP1 expression. Here, we report that NRP1 is preferentially expressed on intratumoral T-regs across six distinct cancer types compared to healthy donor peripheral blood [peripheral blood lymphocyte (PBL)] and site-matched, noncancer tissue. Furthermore, NRP1(+) T-reg prevalence is associated with reduced progression-free survival in head and neck cancer. Human NRP1(+) T-regs have broad activation programs and elevated suppressive function. Unlike mouse T-regs, we demonstrate that NRP1 identifies a transient activation state of human T-regs driven by continuous T cell receptor (TCR) signaling through the mitogen-activated protein kinase pathway and interleukin-2 exposure. The prevalence of NRP1(+) T-regs in patient PBL correlates with the intratumoral abundance of NRP1(+) T-regs 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-reg function in the TME.

Automated summary

Despite the success of immune checkpoint blockade therapy, targeting regulatory T cells (T-regs) within the tumor microenvironment remains a challenge due to the need for specificity to avoid systemic inflammation. Neuropilin-1 (NRP1) is preferentially expressed by intratumoral T-regs and may indicate higher disease burden in patients. NRP1 marks a transient activation state of human T-regs driven by continuous T cell receptor signaling and interleukin-2 exposure.