MS275 induces tumor immunosuppression by up-regulating PD-L1 and enhances the efficacy of anti-PD-1 immunotherapy in colorectal cancer

Abstract

Abstract The histone deacetylase inhibitor MS275 (Entinostat) demonstrates anti-tumor effects against various types of solid tumors in vitro. But its effectiveness in clinical trials is limited. The underlying reasons remain to be determined. The purpose of this study was to explore how to enhance the anti-tumor effects of MS275 in colorectal cancer(CRC). Our data showed that MS275 inhibited CRC cell proliferation and induced apoptosis, irrespective of gene mutation status. However, MS275 did not effectively suppress tumor growth in the AOM-DSS CRC model as observed in vitro. MS275 decreased CD3 + T cell tumor infiltration and created an anti-tumor immunosuppressive microenvironment in the AOM-DSS CRC model. MS275 also decreased the percentage of CD8 + T cells while increasing the percentage of CD4 + T cells in tumor-lymphocyte mixed culture. Reshaping tumor immune response may contribute to the less pronounced anti-tumor effect of MS275 observed in vivo compared to in vitro. Further study show that the increased PD-L1 expression in CRC both in vivo and in vitro following MS275 treatment. Moreover, the anti-tumor effects of MS275 were enhanced by combining it with an anti-PD-1 antibody. This combination treatment also increased CD3 + T cell tumor infiltration and M1 macrophage polarization in the AOM-DSS CRC model, thereby leading to an anti-tumor immune response. Therefore, the combination of MS275 and anti-PD-1 immunotherapy represents a potential strategy for low PD-L1 expression tumors and should be considered a promising treatment approach for colon cancer.