Biomarkers from the tumor microenvironment to predict clinical response to checkpoint inhibitors

Check point inhibitors are a novel class of immunomodulators with ability to reverse the anergy of T-cells in the tumor microenvironment. Two main co-stimulatory inhibitory molecules have been targeted with these molecules: the CTLA-4/CD80-CD86 and the PD-1/PD-L1-PDL-2 axis. Ipilimumab (anti-CTLA-4) inhibits the binding of CTLA-4 to CD80 and CD86 and has been clinically approved for patients with metastatic melanoma. Many clinical trials with antibodies blocking the PD-1/PD-L1 pathways have shown impressive results in patients with metastatic melanoma, renal cell carcinoma, non-small lung cell carcinoma, head and neck cancer, and ovarian cancer. Due to their efficacy in only a subgroup of patients and their major cost, biomarkers allowing a better selection of patient are eagerly awaited. Our group and others showed that expression of checkpoint inhibitors on T-cells in the blood did not reflect their expression in the tumor microenvironment. Up until now no blood biomarker able to predict clinical response to checkpoint inhibitors have been identified. So current studies switched to the analysis of the phenotype of tumor and infiltrating immune cells as predictive biomarker to checkpoint inhibitors efficacy. Expression of PD-L1 in the tumor microenvironment may represent a biomarker to select patients, but its measure has to be standardized. Other emergent biomarkers include the qualitative analysis of the immune cells in the tumor microenvironment and the cross talk between tumor cells and stromal cells locally.