Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 20; pp. 5628 - 5638
• Main Authors: Sierra, Rosa A, Trillo-Tinoco, Jimena, Mohamed, Eslam, Yu, Lolie, Achyut, Bhagelu R, Arbab, Ali, Bradford, Jennifer W, Osborne, Barbara A, Miele, Lucio, Rodriguez, Paulo C
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.10.2017
• Subjects: Animals; Antibodies - immunology; Antibodies - pharmacology; Arginase; Blocking antibodies; Cancer; Cancer immunotherapy; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - therapy; CD8 antigen; Clonal deletion; Female; Humans; Immunological tolerance; Immunoregulation; Immunosuppression; Immunotherapy; Immunotherapy - methods; Immunotherapy, Adoptive - methods; Jagged-1 Protein - antagonists & inhibitors; Jagged-1 Protein - immunology; Jagged1 protein; Lymphocytes; Lymphocytes T; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metastases; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells - immunology; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; NF-κB protein; Nitric-oxide synthase; Signal Transduction; Suppressor cells; T-Lymphocytes - immunology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-0357

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 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 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. .