NRP1 is required for Treg cell tumor infiltration and escape from tumor immune surveillance.

  • Major finding: NRP1 is required for Treg cell tumor infiltration and escape from tumor immune surveillance.

  • Mechanism: Migration of NRP1-positive Treg cells into VEGF-expressing tumors augments tumor growth.

  • Impact: Inhibition of NRP1 may block Treg cell infiltration and restore antitumor immune responses.

Regulatory T (Treg) cells, which are characterized by expression of CD4, CD25, and Foxp3, promote tumor growth by suppressing antitumor immune responses, and high numbers of Treg cells are associated with poor prognosis. However, the mechanisms by which Treg 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 Treg cells, to this process using mice with specific deletion of NRP1 in CD4-positive T cells, including Treg 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 Treg 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 Treg cells. T-cell–specific NRP1 loss did not decrease the overall number of Treg cells or affect their ability to inhibit CD8-positive T cells but instead impaired Treg-cell migration toward VEGF, suggesting that NRP1 is required for Treg 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 Treg cells was reduced in VEGF-deficient tumors as well as in tumors from mice lacking NRP1-positive Treg cells. Importantly, adoptive transfer of NRP1-positive Treg cells reversed the inhibitory effects of NRP1 ablation on tumor growth. These results identify NRP1 as a critical mediator of Treg-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].