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
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (2) Graduate Program of Microbiology and Immunology, University of Pittsburgh
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (2) Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA. (3) Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (4) Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (5) Integrative Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA. (6) Department of Surgery, Division of Surgical Oncology, UPMC Hillman Cancer Center and UPMC Pancreatic Cancer Program, Pittsburgh, PA 15213, USA. (7) Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (8) Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA. (9) Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. (10) Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (11) Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (12) Department Obstetrics and Gynecology, Gynecologic Oncology Division, Medical University of South Carolina, Charleston, SC 29425, USA. (13) Women's Cancer Research Center, Magee-Women's Research Institute and Foundation and Hillman Cancer Center and Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA. (14) Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (15) Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (16) Harold C. Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, TX 75390, USA. (17) Departments of Medicine, Dermatology, and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (18) Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
