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

Autor: Chuckran CA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Cillo AR; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Moskovitz J; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Overacre-Delgoffe A; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Somasundaram AS; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Shan F; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.; Integrative Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA., Magnon GC; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Kunning SR; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Abecassis I; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Zureikat AH; Department of Surgery, Division of Surgical Oncology, UPMC Hillman Cancer Center and UPMC Pancreatic Cancer Program, Pittsburgh, PA 15213, USA., Luketich J; Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Pennathur A; Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Sembrat J; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA., Rojas M; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA., Merrick DT; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Taylor SE; Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Orr B; Department Obstetrics and Gynecology, Gynecologic Oncology Division, Medical University of South Carolina, Charleston, SC 29425, USA., Modugno F; Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; 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., Buckanovich R; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Schoen RE; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Kim S; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Duvvuri U; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Zeh H; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, TX 75390, USA., Edwards R; Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Kirkwood JM; Departments of Medicine, Dermatology, and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Coffman L; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ferris RL; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Bruno TC; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA., Vignali DAA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2021 Dec 08; Vol. 13 (623), pp. eabf8495. Date of Electronic Publication: 2021 Dec 08.
DOI: 10.1126/scitranslmed.abf8495
Abstrakt: 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.
Databáze: MEDLINE