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

Abstract

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.

Keywords: checkpoint inhibitors; immunotherapy; mechanism of action; solid tumors.

Figure 1.

Host-tumor interaction in tumorigenesis. Schematic of the interaction between host immunity and tumor at different points of time during the known phases of immune editing process. The escape phase is a key event before the manifestation of tumor tissue and the moment when the direction of the immune response changes from anti-tumor to pro-tumor.

Figure 2.

Control of tissue homeostasis by regulatory systems. The immune system as one of the regulatory systems is involved in maintaining tissue homeostasis. The morphogenetic function of immunity is realized by controlling the dynamic equilibrium between the processes of cell proliferation, differentiation and apoptosis. All arrows indicate the direction of the regulatory influence.

Figure 3.

Immune regulation of tissue homeostasis in an organ affected by tumor before and after tumor exposure to ICIs. (A) Schematic of central immune system-mediated regulation of homeostasis in normal and tumor tissue in the case of a clinical tumor. An organ affected by cancer consists of tumorous and normal tissue containing Tregs intended for each tissue type. Tissue-specific Tregs dynamically emerge in the thymus in response to signals from the periphery according to the needs of the tissue. T cells begin to differentiate in the thymus and complete differentiation in the peripheral tissue compartment to which they migrate due to innate homing ability. Maturation of T cells in the thymus requires a constant supply of T cell progenitors from bone marrow. Recirculating Treg clones are similar in phenotype and differ only in the direction of migration to the specific tissue, dictated by unique MHC antigens that attract corresponding TCRs. CTLA-4 and PD-1 are functional receptors of Tregs with ligands B-7 and PD-L1, respectively. (B) Schematic of the multilevel mechanism of action of ICIs. Exposure of tumor to ICIs leads to disruption of contact between tumor tissue and immune cells by inhibiting functional receptors on Tregs. Further impairment of tumor tissue homeostasis occurs due to weakening of self-sustaining mechanisms of central immune regulation. The quantitative side (the number of immune checkpoints as targets) of interaction between receptors on immune and on tumor cells and the rate of generation of new clones of tumor-associated T lymphocytes determine the effect of ICIs at the tissue level. ICI, immune checkpoint inhibitor; Treg, T regulatory cell; MHC, major histocompatibility complex; TCR, T-cell receptor; CD, cluster of differentiation; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand-1.