Aiming to determine the role of neuropilin-1 (NRP1) in Tregs, Chuckran et al. analyzed patient samples from six solid tumors and showed that surface-exposed NRP1 is enriched in intratumor Tregs compared to healthy donor peripheral blood and site-matched, non-cancer tissue. TCR signaling through the MAPK pathway and IL-2 exposure drove high surface NRP1 expression in Tregs. NRP1+ Tregs demonstrated higher suppressive potential and were associated with increased FOXP3 expression and decreased PFS in HNSCC. Circulating NRP1+ Tregs in patient PBLs correlated with the intratumoral NRP1+ Tregs and was predictive of poor prognosis in patients.
Contributed by Shishir Pant
ABSTRACT: Despite the success of immune checkpoint blockade therapy, few strategies sufficiently overcome immunosuppression within the tumor microenvironment (TME). Targeting regulatory T cells (Tregs) is challenging, because perturbing intratumoral Treg function must be specific enough to avoid systemic inflammatory side effects. Thus, no Treg-targeted agents have proven both safe and efficacious in patients with cancer. Neuropilin-1 (NRP1) is recognized for its role in supporting intratumoral Treg function while being dispensable for peripheral homeostasis. Nonetheless, little is known about the biology of human NRP1+ Tregs and the signals that regulate NRP1 expression. Here, we report that NRP1 is preferentially expressed on intratumoral Tregs across six distinct cancer types compared to healthy donor peripheral blood [peripheral blood lymphocyte (PBL)] and site-matched, noncancer tissue. Furthermore, NRP1+ Treg prevalence is associated with reduced progression-free survival in head and neck cancer. Human NRP1+ Tregs have broad activation programs and elevated suppressive function. Unlike mouse Tregs, we demonstrate that NRP1 identifies a transient activation state of human Tregs driven by continuous T cell receptor (TCR) signaling through the mitogen-activated protein kinase pathway and interleukin-2 exposure. The prevalence of NRP1+ Tregs in patient PBL correlates with the intratumoral abundance of NRP1+ Tregs 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 Treg function in the TME