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


Sci Transl Med, 2021, 13 (623)

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