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

Rosa A. Sierra, Jimena Trillo-Tinoco, Eslam Mohamed, Lolie Yu, Bhagelu Ram Achyut, Ali Syed Arbab, Jennifer Webster Bradford, Barbara A. Osborne, Lucio Miele, Paulo C. Rodriguez

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Myeloid-derived suppressor cells (MDSC) 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, affected 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 CD8þ 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 coinjection 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.

Original languageEnglish (US)
Pages (from-to)5628-5638
Number of pages11
JournalCancer Research
Volume77
Issue number20
DOIs
StatePublished - Oct 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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