Translational Biomarkers and Rationale Strategies to Overcome Resistance to Immune Checkpoint Inhibitors in Solid Tumors.

Immune checkpoint inhibitors (ICIs) targeting the programed cell-death protein 1 (PD-1) or its ligand PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways have improved the survival for patients with solid tumors. Unfortunately, durable clinical responses are seen in only 10-40% of patients at the cost of potential immune-related adverse events. In the tumor microenvironment (TME), tumor cells can influence the microenvironment by releasing extracellular signals and generating peripheral immune tolerance, while the immune cells can affect the initiation, growth, proliferation, and evolution of cancer cells. Currently, translational biomarkers that predict responses to ICIs include high PD-L1 tumor proportion score, defective DNA mismatch repair, high microsatellite instability, and possibly high tumor mutational burden. Characterization of immune cells in the TME, such as tumor-infiltrating lymphocytes, T-cell gene expression profile, T-cell receptor sequencing, and peripheral blood biomarkers are being explored as promising biomarkers. Recent neoadjuvant studies have integrated the real-time assessment of both molecular and immune biomarkers using the tissue and blood specimens simultaneously and longitudinally. This review summarizes the current knowledge and progress in developing translational biomarkers and rational combinational strategies to improve the efficacy of ICIs tailored to individual cancer patients.