Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance.

Myeloid-derived suppressor cells (MDSCs) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2 blocking antibody CTX014 on MDSC-mediated T cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, impacted the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T cell tolerance, increased the infiltration of reactive CD8+ T-cells into tumors, and enhanced the efficacy of T cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas co-injection of MDSC-like cells from anti-Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy.

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