Immune checkpoint inhibitors in luminal gastrointestinal malignancies: going beyond MSI-H/dMMR, TMB and PD-L1

Abstract

In luminal gastrointestinal tumors, immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 and CTLA-4 have been investigated in multiple settings. The indications for these drugs are primarily dependent on specific biomarkers that imply immunogenicity: overexpression of PD-L1, tumor mutational burden, loss of mismatch repair proteins (dMMR) and/or high microsatellite instability status. Although these markers can be both predictive and prognostic, there is variability in how they are measured and used to guide therapies. Moreover, the use of ICIs can be further refined with a better understanding of the tumor microenvironment and interactions with other available therapies. The purpose of this review is to characterize luminal gastrointestinal tumors' responses to ICIs considering known predictive biomarkers and discuss emerging therapeutic approaches using ICIs.

Keywords: PD-L1; colorectal cancer; esophageal cancer; gastric cancer; immune checkpoint inhibitors; immunotherapy; microsatellite instability; mismatch repair; tumor microenvironment; tumor mutational burden.