Rhein enhances the cytotoxicity of effector lymphocytes in colon cancer under hypoxic conditions.

The immunosuppressive tumor microenvironment limits the application of adoptive immunotherapy for solid tumors. Hypoxia is closely associated with the formation of the immunosuppressive tumor microenvironment. Hypoxia-inducible factor-1 (HIF-1) is an oxygen-sensitive transcriptional activator that drives the transcription of several immunosuppressive molecules. In addition, previous studies confirmed that rhein downregulated the expression of HIF-1α, a subunit of HIF-1, in pancreatic cancer cells. The present study established correlations between mRNA expression levels of HIF-1α and six immunosuppressive molecules in colorectal cancer (CRC) tissue samples. This study examined the effect of rhein on the expression levels of HIF-1α and six immunosuppressive molecules in CRC cell lines under hypoxic conditions by western blot analysis and reverse transcription-quantitative polymerase chain reaction. This study demonstrated that rhein downregulated the expression of HIF-1α and immunosuppressive molecules in CRC cells under hypoxic conditions. In addition, the present study analyzed the cytotoxicity of peripheral blood lymphocytes in vitro using a non-toxic cytotoxicity assay. This study demonstrated that in vitro , rhein enhanced the cytotoxicity of effector lymphocytes toward tumor cells under hypoxic conditions, and therefore rhein may be used in combination with effector lymphocytes for the treatment of CRC.