Regulatory T cells (Treg) are critical to maintenance of self-tolerance and prevention of autoimmunity; however, they also function to limit anti-cancer responses.Therefore, clarifying the mechanisms of Treg-mediated suppression in the context of cancer will aid in the rational design of new therapies.Our lab has identified a novel suppressive role for the IL35 heterodimer in Treg. IL35 is a member of the IL12 family composed of IL12a and Ebi3 subunits and is preferentially expressed by Treg. Treg and other suppressive factors in the tumor microenvironment inhibit antigen-specific cytotoxic lymphocyte responses; depletion or inhibition of Treg has been shown to decrease tumor burden and enhance patient outcome in both animal models and the clinic. We hypothesize that IL35 contributes critically to the tumor microenvironment and that its elimination will enhance tumor specific immunity. Using neutralizing antibodies specific for IL35-Ebi3, we have shown that systemic neutralization of IL35 significantly slows tumor growth compared with IgG control and enhances survival in the B16 melanoma model. Molecular analysis of tumor-infiltrating lymphocytes (TILs) has shown increased numbers, more activated CD8+ cells (CD44+CD62L-), and a greater proportion of proliferative cells by BrdU/Ki-67 staining in IL35-neutralized animals. We are currently extending studies to include metastatic and genetic models to better understand the mechanism of IL35 activity in the tumor microenvironment.
- Copyright © 2013 by The American Association of Immunologists, Inc.