Anti-CTLA-4 Response In Mouse Tumor Syngeneic Models

In order to improve the benefit of anti-CTLA4 immunotherapy the current challenges the pharma industry are facing are the:
  • Development and evaluation of novel test compounds able to synergize with anti-CTLA-4
  • Discovery of novel molecular mechanisms underlying the resistance to anti-CTLA4 blockade
  • Identification of biomarkers capable to predict response to anti-CTLA4 therapy

At a preclinical stage, these points can be addressed using immunocompetent animal models in which the response to reference immune checkpoint inhibitors is validated. This is why we characterized the clinical response to anti-CTLA4 immunotherapy in mouse syngeneic tumor models and selected the most sensitive to further investigate the cellular and molecular features of the immune response associated with clinical efficacy.

Focus On The Characterization Of The Immune Response

 Anti-CTLA-4 Response In Mouse Tumor Syngeneic Models
anti-CTLA-4 modulates splenic myeloid suppressive cells (MDSC) from CT26 tumor bearing mice but not regulatory T cells (TReg) from tumor draining lymph nodes (TDLN). 
Spleens and Tumor Draining Lymph nodes were harvested and processed for flow cytometry analysis. Upper scatter plots show CD11b and Gr1 stainings and particularly the CD11b+ Gr1Low Myeloid Derived Suppressor cells (MDSC). Further quantification demonstrates that spleen from CT26 tumor bearing mice present a higher percentage of suppressive cells, which are drastically affected upon CTLA4 treatment. In contrast, lower scatter plots show CD4 and FoxP3 stainings and further quantification demonstrates that CTLA4 treatment do not affect the CD4+ FoxP3+ cells.
  • Increase in regulatory T cells (CD4+ FoxP3+) is observed in tumor draining lymph nodes from CT26 tumor bearing mice but is not affected upon anti-CTLA4 antibody
  • Increase in myeloid suppressive cells (CD11b+ Gr1Low & CD11b+ CD11cHigh) is found in spleen from CT26 tumor bearing mice and is significantly abolished by anti-CTLA4 antibody
  • Further gene expression analysis by RT-qPCR is included in the full case study and shows that CTLA4 blockade affect key genes either in tumor draining lymph nodes and in dendritic cells

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