Regulatory T cells (Tregs) inhibit beneficial antitumor responses. Treg depletion enhances tumor rejection in animal models and the clinic but also leads to substantial adverse events. Thus approaches have been sought to target Tregs in tumors while limiting systemic autoimmune and inflammatory manifestations. Two approaches will be discussed. First, the signals that maintain Treg stability and potentiate their function remain obscure. We have shown that the immune cell surface ligand semaphorin-4a (Sema4a) on conventional T cells and DCs, and the Treg-restricted receptor neuropilin-1 (Nrp1) interact to potentiate Treg function. Mice with a Treg-restricted deletion of Nrp1 exhibit limited tumor-induced tolerance and thus substantial resistance to tumors, yet do not develop any autoimmune manifestations. Thus, Nrp1 ligation maintains Treg stability and function in highly inflammatory sites but is dispensable for the maintenance of immune homeostasis, highlighting Nrp1 as a potential immunotherapeutic target in cancer. Second, the relative importance of different Treg suppressive mechanisms remains contentious. Interleukin-35 (IL35) is a Treg-secreted cytokine known to inhibit effector T cell proliferation and mediate infectious tolerance via induction of suppressive IL35-producing induced Tregs, iTr35. Using antibody-mediated neutralization, Treg-restricted deletion of Ebi3 and novel reporter mice, we have shown that IL35 facilitated tumor growth by limiting antitumor immunity in transplantable and genetically-induced murine models of melanoma and lung carcinoma. These findings reveal the previously unappreciated importance of IL35 in limiting antitumor immunity and present IL35 as a potential therapeutic target in cancer.

Citation Format: Dario A. Vignali. Targeting regulatory T cells in tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA05.