C/EBP homologous protein expression regulates immunosuppressive activity in myeloid derived suppressor cells (TUM6P.1006)

Abstract

Abstract Myeloid-derived suppressor cell (MDSC) suppression of anti-tumor T cell responses is a significant barrier in cancer immunotherapy. Although pathways controlling MDSC regulatory activity have been characterized, therapies to globally and specifically inhibit MDSC function are limited. Targeting central mediators of MDSC-regulatory activity may overcome T cell suppression and increase the efficacy of T cell-based immunotherapy. We investigated the role of the stress sensor C/EBP homologous protein (Chop) on MDSC function. Elevated Chop expression in tumor-bearing mice was restricted to malignant cells and tumor MDSCs. Chop elevation was also detected in tumor MDSCs from colon carcinoma patients. Interestingly, increased CD8+ T cell-mediated anti-tumor effects were found in both systemic Chop -/- and Chop -/- bone marrow chimeric mice bearing s.c. Chop-competent tumors, suggesting the importance of MDSC-Chop in tumor-induced T cell anergy. MDSCs from Chop -/- mice showed a decreased expression of major MDSC-inhibitory pathways, reduced inhibitory activity on T cells, and a surprising ability to prime T cell proliferation and induce anti-tumor effects. The reduced regulatory activity in Chop -/- MDSCs was caused by decreased IL-6 production, resulting from decreased C/EBPb activity. Altogether the results demonstrate a central role of Chop in MDSC inhibitory activity and suggest targeting Chop to restore protective immunity in cancer.