Soluble immune checkpoints in cancer: production, function and biological significance

Abstract

Immune checkpoints play important roles in immune regulation, and blocking immune checkpoints on the cell membrane is a promising strategy in the treatment of cancer. Based on this, monoclonal antibodies are having much rapid development, such as those against CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein 1).But the cost of preparation of monoclonal antibodies is too high and the therapeutic effect is still under restrictions. Recently, a series of soluble immune checkpoints have been found such as sCTLA-4 (soluble CTLA-4) and sPD-1 (soluble PD-1). They are functional parts of membrane immune checkpoints produced in different ways and can be secreted by immune cells. Moreover, these soluble checkpoints can diffuse in the serum. Much evidence has demonstrated that these soluble checkpoints are involved in positive or negative immune regulation and that changes in their plasma levels affect the development, prognosis and treatment of cancer. Since they are endogenous molecules, they will not induce immunological rejection in human beings, which might make up for the deficiencies of monoclonal antibodies and enhance the utility value of these molecules. Therefore, there is an increasing need for investigating novel soluble checkpoints and their functions, and it is promising to develop relevant therapies in the future. In this review, we describe the production mechanisms and functions of various soluble immune checkpoint receptors and ligands and discuss their biological significance in regard to biomarkers, potential candidate drugs, therapeutic targets, and other topics.

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

“…ICP molecules also exist in soluble forms. Similar to membrane‐bound ICPs (mICPs), soluble ICPs (sICPs) are also present in normal physiologic conditions and are highly dysregulated in patients with cancer or various inflammatory diseases . Soluble ICPs can be generated through either alternative messenger RNA (mRNA) splicing and secretion, extracellular release of membrane‐bound receptors from exosomes, or protease‐mediated shedding from mICPs by actions of matrix metalloproteinases (MMPs).…”

“…Soluble ICPs can be generated through either alternative messenger RNA (mRNA) splicing and secretion, extracellular release of membrane‐bound receptors from exosomes, or protease‐mediated shedding from mICPs by actions of matrix metalloproteinases (MMPs). Some, if not all, sICPs exhibit biological functions as decoy receptors/ligands for mICPs or as agonists to positively or negatively regulate immune responses . Levels of circulating sICPs are often elevated in cancer and inflammatory diseases, serving as promising prognostic and/or predictive biomarkers …”

“…Similar to membrane-bound ICPs (mICPs), soluble ICPs (sICPs) are also present in normal physiologic conditions and are highly dysregulated in patients with cancer or various inflammatory diseases. (12)(13)(14)(15)(16) Soluble ICPs can be generated through either alternative messenger RNA (mRNA) splicing and secretion, extracellular release of membrane-bound receptors from exosomes, or protease-mediated shedding from mICPs by actions of matrix metalloproteinases (MMPs). Some, if not all, sICPs exhibit biological functions as decoy receptors/ligands for mICPs or as agonists to positively or negatively regulate immune responses.…”

“…Some, if not all, sICPs exhibit biological functions as decoy receptors/ligands for mICPs or as agonists to positively or negatively regulate immune responses. (16)(17)(18) Levels of circulating sICPs are often elevated in cancer and inflammatory diseases, serving as promising prognostic and/or predictive biomarkers. (16) Currently, there are no systematic studies of either mICPs or sICPs in patients with AH.…”

“…(16)(17)(18) Levels of circulating sICPs are often elevated in cancer and inflammatory diseases, serving as promising prognostic and/or predictive biomarkers. (16) Currently, there are no systematic studies of either mICPs or sICPs in patients with AH. Given that ICPs are the key regulators of immune responses and that patients with AH are in a highly immunedysregulated state, ICP axes are likely dysregulated in patients with AH.…”