Prevalence 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<sub>regs</sub>) is challenging, because perturbing intratumoral T<sub>reg</sub> function must be specific enough to avoid systemic inflammatory side effects. Thus, no T<sub>reg</sub>-targeted agents have proven both safe and efficacious in patients with cancer. Neuropilin-1 (NRP1) is recognized for its role in supporting intratumoral T<sub>reg</sub> function while being dispensable for peripheral homeostasis. Nonetheless, little is known about the biology of human NRP1<sup>+</sup> T<sub>regs</sub> and the signals that regulate NRP1 expression. Here, we report that NRP1 is preferentially expressed on intratumoral T<sub>regs</sub> across six distinct cancer types compared to healthy donor peripheral blood [peripheral blood lymphocyte (PBL)] and site-matched, noncancer tissue. Furthermore, NRP1<sup>+</sup> T<sub>reg</sub> prevalence is associated with reduced progression-free survival in head and neck cancer. Human NRP1<sup>+</sup> T<sub>regs</sub> have broad activation programs and elevated suppressive function. Unlike mouse T<sub>regs</sub>, we demonstrate that NRP1 identifies a transient activation state of human T<sub>regs</sub> driven by continuous T cell receptor (TCR) signaling through the mitogen-activated protein kinase pathway and interleukin-2 exposure. The prevalence of NRP1<sup>+</sup> T<sub>regs</sub> in patient PBL correlates with the intratumoral abundance of NRP1<sup>+</sup> T<sub>regs</sub> 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<sub>reg</sub> function in the TME.

  • Abecassis I
  • Bruno TC
  • Buckanovich R
  • Chuckran CA
  • Cillo AR
  • Coffman L
  • Duvvuri U
  • Edwards R
  • Ferris RL
  • Kim S
  • Kirkwood JM
  • Kunning SR
  • Luketich J
  • Magnon GC
  • Merrick DT
  • Modugno F
  • Moskovitz J
  • Orr B
  • Overacre-Delgoffe A
  • Pennathur A
  • Rojas M
  • Schoen RE
  • Sembrat J
  • Shan F
  • Somasundaram AS
  • Taylor SE
  • Vignali DAA
  • Zeh H
  • Zureikat AH
PubMed ID
Appears In
Sci Transl Med, 2021, 13 (623)