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

Christopher A. Chuckran, Anthony R. Cillo, Jessica Moskovitz, Abigail Overacre-Delgoffe, Ashwin S. Somasundaram, Feng Shan, Grant C. Magnon, Sheryl R. Kunning, Irina Abecassis, Amer H. Zureikat, James Luketich, Arjun Pennathur, John Sembrat, Mauricio Rojas, Daniel T. Merrick, Sarah E. Taylor, Brian Orr, Francesmary Modugno, Ron Buckanovich, Robert E. SchoenSeungwon Kim, Umamaheswar Duvvuri, Herbert Zeh, Robert Edwards, John M. Kirkwood, Lan Coffman, Robert L. Ferris, Tullia C. Bruno, Dario A.A. Vignali

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article numbereabf8495
JournalScience translational medicine
Volume13
Issue number623
DOIs
StatePublished - Dec 8 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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