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 journalArticle

14 Citations (Scopus)

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

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Immunotherapy
Neoplasms
T-Lymphocytes
Myeloid-Derived Suppressor Cells
Growth
Arginase
Blocking Antibodies
Therapeutic Uses
Immunosuppressive Agents

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sierra, R. A., Trillo-Tinoco, J., Mohamed, E., Yu, L., Achyut, B. R., Arbab, A. S., ... Rodriguez, P. C. (2017). Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance. Cancer Research, 77(20), 5628-5638. https://doi.org/10.1158/0008-5472.CAN-17-0357

Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance. / Sierra, Rosa A.; Trillo-Tinoco, Jimena; Mohamed, Eslam; Yu, Lolie; Achyut, Bhagelu Ram; Arbab, Ali Syed; Bradford, Jennifer Webster; Osborne, Barbara A.; Miele, Lucio; Rodriguez, Paulo C.

In: Cancer Research, Vol. 77, No. 20, 15.10.2017, p. 5628-5638.

Research output: Contribution to journalArticle

Sierra, RA, Trillo-Tinoco, J, Mohamed, E, Yu, L, Achyut, BR, Arbab, AS, Bradford, JW, Osborne, BA, Miele, L & Rodriguez, PC 2017, 'Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance', Cancer Research, vol. 77, no. 20, pp. 5628-5638. https://doi.org/10.1158/0008-5472.CAN-17-0357
Sierra, Rosa A. ; Trillo-Tinoco, Jimena ; Mohamed, Eslam ; Yu, Lolie ; Achyut, Bhagelu Ram ; Arbab, Ali Syed ; Bradford, Jennifer Webster ; Osborne, Barbara A. ; Miele, Lucio ; Rodriguez, Paulo C. / Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance. In: Cancer Research. 2017 ; Vol. 77, No. 20. pp. 5628-5638.
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