Neuropilin-1 enforces Treg stability and function in the tumor microenvironment. (TUM2P.889)

Abstract

Abstract Regulatory T cells (Tregs) play an integral role in the adaptive immune system by suppressing detrimental self-reactive responses. However, Tregs have deleterious effects in cancer through suppression of the anti-tumor immune response. Therefore, it is advantageous to understand the role of Tregs in the tumor microenvironment in order to create targeted cancer therapies. Our lab has uncovered a novel function for neuropilin-1 (Nrp1) on Tregs in tumors. In the absence of Nrp1 ligation by its ligand, Sema4a, Tregs lose stability and suppressive capabilities, leading to enhanced anti-tumor immunity and reduced tumor growth or tumor clearance. We hypothesize that the loss of Nrp1 expression on Tregs reduces intratumoral stability through altered intracellular pathways and diminished Foxp3 expression, transforming Tregs from an anti-inflammatory to a pro-inflammatory T cell population. Nrp1-deficient Tregs have a hypermethylated Foxp3 CNS2/TSDR locus in the tumor microenvironment, comparable to Teff, and display TH1-like characteristics, with upregulation of Tbet, CXCR3, and IFNγ, and the reduction of suppressive molecules, IL-10 and CD73. Furthermore, in competitive environments Nrp1-deficient Tregs undermine and limit the function of wild-type Tregs. Further mechanistic analysis and fate mapping studies will elucidate the cell-intrinsic and cell-extrinsic impact of Nrp1 loss on Treg function and tumor clearance.