Neuropilin 1 Mediates T_reg cell Recruitment and Enhances Tumor Growth

Regulatory T (T_reg) cells, which are characterized by expression of CD4, CD25, and Foxp3, promote tumor growth by suppressing antitumor immune responses, and high numbers of T_reg cells are associated with poor prognosis. However, the mechanisms by which T_reg cells infiltrate tumors to trigger immune escape are unclear. Hansen and colleagues investigated the contribution of neuropilin 1 (NRP1), a VEGF receptor that is highly expressed in T_reg cells, to this process using mice with specific deletion of NRP1 in CD4-positive T cells, including T_reg cells. NRP1 ablation significantly diminished the growth of subcutaneous xenografts and spontaneous melanomas in a transgenic mouse model, similar to the effects of depleting Foxp3-positive T_reg cells. This reduction in tumor growth was accompanied by intratumoral accumulation of activated CD8-positive effector T cells, indicating that antitumor immune responses are restored in the absence of NRP1-expressing T_reg cells. T-cell–specific NRP1 loss did not decrease the overall number of T_reg cells or affect their ability to inhibit CD8-positive T cells but instead impaired T_reg-cell migration toward VEGF, suggesting that NRP1 is required for T_reg cell infiltration into VEGF-expressing tumors. In support of this idea, deletion of tumor-derived VEGF expression resulted in increased CD8-positive T-cell activation and reduced tumor growth in wild-type mice. Furthermore, the number of tumor-infiltrating Foxp3-positive T_reg cells was reduced in VEGF-deficient tumors as well as in tumors from mice lacking NRP1-positive T_reg cells. Importantly, adoptive transfer of NRP1-positive T_reg cells reversed the inhibitory effects of NRP1 ablation on tumor growth. These results identify NRP1 as a critical mediator of T_reg-cell–mediated tumor immune escape and suggest that blocking this receptor may reestablish antitumor immune responses to reduce tumor growth.

Hansen W, Hutzler M, Abel S, Alter C, Stockmann C, Kliche S, et al. Neuropilin 1 deficiency on CD4⁺Foxp3⁺ regulatory T cells impairs mouse melanoma growth. J Exp Med 2012 October 8 [Epub ahead of print].