Multilevel mechanism of immune checkpoint inhibitor action in solid tumors: History, present issues and future development.

Immunotherapy with checkpoint inhibitors (antibodies that target and block immune checkpoints in the tumor microenvironment) is included in the standard of care for patients with different types of malignancy, such as melanoma, renal cell and urothelial carcinoma, lung cancer etc. The introduction of this new immunotherapy has altered the view on potential targets for treatment of solid tumors from tumor cells themselves to their immune microenvironment; this has led to a reconsideration of the mechanisms of tumor-associated immunity. However, only a subset of patients benefit from immunotherapy and patient response is often unpredictable, even with known initial levels of prognostic markers; the biomarkers for favorable response are still being investigated. Mechanisms of immune checkpoint inhibitors efficiency, as well as the origins of treatment failure, require further investigation. From a clinical standpoint, discrepancies between the theoretical explanation of inhibitors of immune checkpoint actions at the cellular level and their deployment at a tissue/organ level impede the effective clinical implementation of novel immune therapy. The present review assessed existing experimental and clinical data on functional activity of inhibitors of immune checkpoints to provide a more comprehensive picture of their mechanisms of action on a cellular and higher levels of biological organization.