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Protein kinase inhibitor-mediated immunoprophylactic and immunotherapeutic control of colon cancer

ABSTRACT: An innovative multikinase inhibitor (H89)-based antitumor immunotherapy in colorectal cancer (CRC) is presented. The study was designed to evaluate the effect of H89 on colon tumor growth and carcinogenesis through in vivo analyses. Syngeneic mouse models of CRC cancer in BALB/c mice and chemically colon tumorigenesis, reveals that H89 delays colon oncogenesis, related to a preventive effect, and prevents tumor growth, underlying an antitumor effect respectively. Using immunodeficient and monoclonal antibody-specific immunosuppression, we identified immune cell populations involved in the preventive (NK-cell dependent) and antitumor activity of H89 (T-cell dependent). Flow cytometry analysis showed that the antitumor effect of H89 was correlated with an increase in the tumor microenvironment of CD4+ Th1 cells and CD8+ cytotoxic T cells and a decrease of CD4+ Treg cells infiltration. Furthermore, qRT-PCR revealed that H89 can promote naïve CD4+ T cells differentiation into Th1, decreases Treg differentiation and increases ex vivo CD8+ T cell-mediated killing of cancer cells. An RNAseq profiling experiment showed that H89 induces an overexpression of genes involved in antitumor immune response, such as IL-15RA, whose inhibition counteracts the antitumor effect of H89. In conclusion, our findings identify H89 as a potential strategy for the prevention and treatment of CRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE197598 | GEO | 2022/03/03

REPOSITORIES: GEO

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