An Analysis of the Effect of Tryptophan Metabolites on the Programmed Death Ligand-1 in Colorectal Cancer Cells

Abstract

Colorectal cancer (CRC) is a major public health concern, with early onset CRC cases rapidly increasing annually. Early onset CRC is characterized by mismatch repair deficiency (dMMR) and influenced by the gut microbiome, two factors which may impact success of immunotherapy treatments. Specifically, immunotherapy targeting the immune evasion checkpoint, programmed death receptor PD-1/PD-L1, is more successful in patients with dMMR. In addition, the gut microbiome is a known contributor to PD-1/PD-L1 blockade success. PD-L1 expression may be impacted by the gut microbiome via microbial-derived tryptophan metabolites interacting with the aryl hydrocarbon receptor. This study explores the impact of metabolites that exist at higher levels in the CRC microenvironment, indole-3-aldehyde (I3A) and indole-3-carboxylic acid (I3CA), on PD-L1 expression. The hypothesis of this study is that these bacterial derived indoles change the expression of PD-L1 in vitro. This study found that PD-L1 expression was significantly lowered in colon cancer (HT29) cells treated with I3CA, but not other indole variants, suggesting that gut microbiome derived indole variants may impact immunotherapy responses in CRC.