Data from A Neuropilin-1 Antagonist Exerts Antitumor Immunity by Inhibiting the Suppressive Function of Intratumoral Regulatory T Cells

Abstract

<div>Abstract<p>Regulatory T cells (Treg) are targeted for cancer immunotherapy because they suppress antitumor immunity. Although the importance of neuropilin-1 (NRP1) in the stability and function of intratumoral Tregs is well-documented, targeting of NRP1<sup>+</sup> Tregs for anticancer immunotherapy has not been well explored. Here, we found that an NRP1 antagonist [Fc(AAG)-TPP11], generated by fusion of the NRP1-specific binding peptide TPP11 with the C-terminus of an effector function–deficient immunoglobulin Fc(AAG) variant, inhibits intratumoral NRP1<sup>+</sup> Treg function and stability. Fc(AAG)-TPP11 triggered the internalization of NRP1, reducing its surface expression on Tregs and thereby inhibiting the suppressive function of Tregs. In two murine syngeneic tumor models, Fc(AAG)-TPP11 retarded tumor growth, comparable with a Treg-depleting anti–CTLA-4 antibody, without noticeable toxicity. Fc(AAG)-TPP11 inhibited NRP1-dependent Treg function, inducing unstable intratumoral Tregs, with reduced expression of Foxp3 and enhanced production of IFNγ, which subsequently increased the functionality and frequency of intratumoral CD8<sup>+</sup> T cells. We also observed selective expression of NRP1 on Tregs isolated from human tumors, but not from the blood of healthy donors and patients with cancer, as well as <i>ex vivo</i> inhibition of intratumoral NRP1<sup>+</sup> Treg function by Fc(AAG)-TPP11. Our results suggest that the NRP1 antagonist Fc(AAG)-TPP11 has therapeutic potential for the inhibition of intratumoral NRP1<sup>+</sup> Tregs with limited unfavorable effects on peripheral Tregs.</p></div>