AUTHOR=Ghione Silvia , Racoeur Cindy , Mabrouk Nesrine , Shan Jingxuan , Groetz Emma , Ballot Elise , Truntzer Caroline , Chouchane Lotfi , Végran Frédérique , Paul Catherine , Plenchette Stéphanie , Bettaieb Ali 

TITLE=Protein Kinase Inhibitor-Mediated Immunoprophylactic and Immunotherapeutic Control of Colon Cancer

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.875764

DOI=10.3389/fimmu.2022.875764

ISSN=1664-3224

ABSTRACT=Immunotherapy has allowed major advances in oncology in the past years, in particular with the development of the immune checkpoint inhibitors, but the clinical benefits are still limited, particularly in colorectal cancer (CRC). Our scientific approach is based on the search for an innovative immunotherapy with a final goal that aims to induce an effective antitumor immune response in CRC. Here we focused on a multikinase inhibitor, H89. We carried out in vivo experiments based on syngeneic mouse models of colon cancer in BALB/c mice and chemically colon tumorigenesis. Flow cytometry, RNAseq, RT-qPCR, antibody-specific immune cell depletion, and Western blot were used to identify the immune cell type involved in the preventive and antitumor activity of H89. We demonstrated that H89 delays colon oncogenesis and prevents tumor growth. This later effect seems to involve NK cells. H89 also inhibits colon tumor growth in a T-cells-dependent manner. Analysis of the immune landscape in the tumor microenvironment showed an increase of CD4+ Th1 cells and CD8+ cytotoxic T cells, but a decrease of CD4+ Treg cells infiltration. Mechanistically, we showed that H89 can promote naïve CD4+ T cells differentiation into Th1, decreases Treg differentiation and increases CD8+ T cells activation and cytotoxicity ex-vivo. Further, H89 induced an overexpression of genes involved in antitumor immune response, such as IL-15RA, which depletion counteracts the antitumor effect of H89. We also found that H89 regulated Akt/PP2A pathway axis, involved in TCR and IL-15 signaling transduction. Our findings identify the H89 as a potential strategy for immune system activation leading to the prevention and treatment of CRC.