Predictive molecular markers in the era of immunotherapy

Abstract

Abstract Recent development in anticancer therapeutics has been centered on immune checkpoint inhibitors (ICIs). Despite early success of ICIs in several cancer types, majority of cancer patients do not respond to ICI therapy. Therefore, predictive biomarkers are urgently needed to select patients who would likely benefit from ICI therapy. Currently immunohistochemical (IHC) assay for programmed cell death ligand 1 (PD-L1) and microsatellite instability (MSI) testing are the only Food and Drug Administration-approved predictive biomarkers for ICI therapies. Tumor mutation burden (TMB) and tumor infiltrating lymphocytes (TILs) are emerging markers, which may prove to be useful predictive markers for ICIs. The guidelines for MSI testing have been well established. However, rigorous quality controls and systemic standardization for PD-L1 IHC testing and analysis of TMB and TILs, such as sample selection, tissue fixation, assay/platform selection, scoring methods, and clinically meaningful cutoff values etc. are needed to improve their clinical utility as predictive biomarkers for ICI therapy. Studies have suggested that the results of PD-L1 expression in tumor cells from various PD-L1 IHC assays are concordant and may be interchangeable. However, the variations and poor interobserver concordance of PD-L1 expression in immune cells is a major issue to be addressed for the interchangeability of different PD-L1 IHC assays, especially for carcinomas of the gastrointestinal tract. Development of new predictive biomarkers and better understanding the difference in tumor immune microenvironments between ICI-sensitive and ICI-resistant tumors will help to develop more effective strategies for immunotherapy.