biostudies-literatureChuckran CANCATS NIH HHSNIAID NIH HHSNCI NIH HHSeabf8495https://www.ebi.ac.uk/biostudies/studies/S-EPMC9022491biostudies-literatureUnknown13(623)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.Science translational medicinePrevalence of intratumoral regulatory T cells expressing neuropilin-1 is associated with poorer outcomes in patients with cancer.PMC9022491P50 CA121973P30 CA047904U01 CA152753P50 CA097190P01 AI108545P50 CA159981F31 CA243168T32 CA060397R01 CA203689UL1 TR001857Shan FBuckanovich RMerrick DTKunning SRCillo ARZeh HSchoen REMagnon GCKirkwood JMMoskovitz JSembrat JAbecassis IZureikat AHRojas MEdwards ROveracre-Delgoffe APennathur ALuketich JDuvvuri UFerris RLChuckran CAKim SSomasundaram ASVignali DAABruno TCModugno FCoffman LTaylor SEOrr BfalsePrevalence 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.2021-01-01T00:00:00Z2021 Dec2024-11-11T19:01:09.866Z2024-11-11T19:01:09.866ZS-EPMC90224913487882110.1126/scitranslmed.abf8495