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Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance
Rosa A Sierra1, Jimena Trillo-Tinoco1, Eslam Mohamed1
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
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 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. Cancer Res; 77(20); 5628-38. ©2017 AACR.
Insights
Targeting Jagged1/2 with the antibody CTX014 effectively reduced myeloid-derived suppressor cells (MDSC) in tumors. This approach enhanced T-cell immunotherapy efficacy by overcoming tumor-induced immune suppression.
Area of Science:
- Immunology
- Cancer Biology
- Therapeutics
Background:
- Myeloid-derived suppressor cells (MDSC) impede effective cancer immunotherapy.
- Current therapeutic strategies to counteract MDSC immunoregulatory functions are limited.
- MDSCs contribute to tumor immune evasion and therapeutic resistance.
Purpose of the Study:
- To evaluate the therapeutic potential of the anti-Jagged1/2 antibody CTX014 against MDSC-mediated T-cell suppression.
- To investigate the impact of CTX014 on MDSC accumulation, function, and immunosuppressive factor expression in tumors.
- To determine if anti-Jagged1/2 therapy can enhance T-cell responses and improve cancer immunotherapy outcomes.
Main Methods:
- Utilized a humanized anti-Jagged1/2-blocking antibody (CTX014) in tumor-bearing mouse models.
- Assessed tumor growth, MDSC accumulation, and tolerogenic activity.
- Measured expression of immunosuppressive factors (arginase I, iNOS) and T-cell infiltration (CD8+).
- Investigated the role of NF-κB signaling in Jagged1/2 induction in MDSCs.
Main Results:
- CTX014 treatment significantly decreased tumor growth.
- The antibody reduced MDSC accumulation and their tolerogenic activity within tumors.
- CTX014 inhibited the expression of arginase I and iNOS, key immunosuppressive factors.
- Anti-Jagged1/2 therapy reversed tumor-induced T-cell tolerance and increased CD8+ T-cell infiltration.
- Depletion of MDSCs restored tumor growth, confirming their role in anti-Jagged therapy resistance.
- Jagged1/2 expression in MDSCs was induced by tumor factors via NF-κB-p65 signaling.
Conclusions:
- Anti-Jagged1/2 antibody therapy represents a promising strategy to reprogram MDSC-mediated T-cell suppression in the tumor microenvironment.
- This approach holds potential for broadly enhancing the efficacy of various cancer immunotherapies.
- Targeting the Jagged1/2-MDSC axis offers a novel therapeutic avenue for overcoming cancer immune evasion.
