Immune responses are finely regulated by a vast array of stimulatory and inhibitory pathways called “immune checkpoints”. Molecules such as PD-1, CTLA4 and their ligands have come to prominence as targets for anti-cancer immunotherapy, but other checkpoint pathways have also demonstrated key roles in the immunopathogenesis of human disease.
Traditionally, immune checkpoints are considered to be cell membrane-bound systems of receptors and ligands able to switch on or off immune cell functions, but it is now becoming clear that immune checkpoints also exist as soluble forms. Far from being simple byproducts of proteolytic degradation, these soluble checkpoints may be biologically active molecules and participate in the paracrine regulation of immune responses similar to stimulatory or inhibitory cytokines.
The association between systemic levels of soluble checkpoints and disease in humans, and their possible use as diagnostic/prognostic disease biomarkers is supported by extensive evidence. However, the experimental work dedicated to clarifying the origin and actual biological properties of soluble checkpoints in humans is scant. Specifically, conclusive evidence on the following points remains outstanding:
(i) molecular mechanism(s) leading to the generation of a specific soluble checkpoint (alternative splicing, membrane ectodomain shedding, proteolytic cleavage);
(ii) biological activity of a specific soluble checkpoint (stimulators vs inhibitors) and whether this biological activity matches or not the biological activity of the respective membrane-bound form(s);
(iii) mechanism(s) of action (binding partners, signal transduction, formation of soluble complexes between soluble receptor and soluble ligands, etc.);
(iv) existence and detection of a specific soluble checkpoint as a single isoform or a molecular mixture of different isoforms;
(v) relative balance of different soluble isoforms in health and disease;
(vi) differential biological properties and activity of different soluble isoforms;
(vii) immunomodulatory functions of recombinant soluble checkpoints.
It is clear that these molecular details may have crucial pathophysiological implications and based on specific experimental results this may support the therapeutic use of soluble checkpoints as novel immunomodulatory pharmacological targets.
The goal of this Research Topic is to collect experimental evidence to answer one or more of the open questions listed above. Ideally, we are seeking to collect results from human studies, as the translational aspects of this research should be focused on human physiology and human disease. We particularly welcome Original Research articles with a robust experimental design, Mini Reviews and Reviews summarizing existing evidence in human health and disease will also be considered. Experimental evidence and reviews from animal studies are outside the scope of this Research Topic but may be accepted if presented as additional supporting evidence in studies centered around human physiology and pathology.
Prof. Tony Bruns received honoraria from Intercept Pharmaceuticals, Falk Foundation, AbbVie, CSL Behring, and Norgine, and financial support from Gilead. The other Topic Editors declare no competing interests with regard to the Research Topic subject.
Immune responses are finely regulated by a vast array of stimulatory and inhibitory pathways called “immune checkpoints”. Molecules such as PD-1, CTLA4 and their ligands have come to prominence as targets for anti-cancer immunotherapy, but other checkpoint pathways have also demonstrated key roles in the immunopathogenesis of human disease.
Traditionally, immune checkpoints are considered to be cell membrane-bound systems of receptors and ligands able to switch on or off immune cell functions, but it is now becoming clear that immune checkpoints also exist as soluble forms. Far from being simple byproducts of proteolytic degradation, these soluble checkpoints may be biologically active molecules and participate in the paracrine regulation of immune responses similar to stimulatory or inhibitory cytokines.
The association between systemic levels of soluble checkpoints and disease in humans, and their possible use as diagnostic/prognostic disease biomarkers is supported by extensive evidence. However, the experimental work dedicated to clarifying the origin and actual biological properties of soluble checkpoints in humans is scant. Specifically, conclusive evidence on the following points remains outstanding:
(i) molecular mechanism(s) leading to the generation of a specific soluble checkpoint (alternative splicing, membrane ectodomain shedding, proteolytic cleavage);
(ii) biological activity of a specific soluble checkpoint (stimulators vs inhibitors) and whether this biological activity matches or not the biological activity of the respective membrane-bound form(s);
(iii) mechanism(s) of action (binding partners, signal transduction, formation of soluble complexes between soluble receptor and soluble ligands, etc.);
(iv) existence and detection of a specific soluble checkpoint as a single isoform or a molecular mixture of different isoforms;
(v) relative balance of different soluble isoforms in health and disease;
(vi) differential biological properties and activity of different soluble isoforms;
(vii) immunomodulatory functions of recombinant soluble checkpoints.
It is clear that these molecular details may have crucial pathophysiological implications and based on specific experimental results this may support the therapeutic use of soluble checkpoints as novel immunomodulatory pharmacological targets.
The goal of this Research Topic is to collect experimental evidence to answer one or more of the open questions listed above. Ideally, we are seeking to collect results from human studies, as the translational aspects of this research should be focused on human physiology and human disease. We particularly welcome Original Research articles with a robust experimental design, Mini Reviews and Reviews summarizing existing evidence in human health and disease will also be considered. Experimental evidence and reviews from animal studies are outside the scope of this Research Topic but may be accepted if presented as additional supporting evidence in studies centered around human physiology and pathology.
Prof. Tony Bruns received honoraria from Intercept Pharmaceuticals, Falk Foundation, AbbVie, CSL Behring, and Norgine, and financial support from Gilead. The other Topic Editors declare no competing interests with regard to the Research Topic subject.
