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