Immune checkpoint inhibitors (ICI) have radically changed the clinical course of many advanced solid tumors. In particular, PD-1 inhibitors interfere with the interaction between PD-1 and its ligand, expressed by tumor cells, inducing apoptosis.
Several recent evidences show that glucocorticoids (GCs) are able to increase PD-1 expression on lymphocytes and natural killer (NK) cells with an immunosuppressive effect. PD-1 activation, in fact, play a key role in maintaining immunological self-tolerance and inhibiting immune response. This effect seems to be also mediated by some cytokines (IL-12, IL-15 and IL-18) that are numerous in the tumor microenvironment.
Starting from this assumption, we designed a study aimed to investigate PD-1 expression on peripheral blood mononuclear cells (PBMC) and IL-12, IL-15 and IL-18 concentration in patients with Cushing's Syndrome (CS) compared with healthy controls. CS, indeed, represents a peculiar and unique prototype of endogenous GCs hypersecretion. Patients enrolled in the study will also undergo a complete hormonal assessment, infectious diseases and quality of sleep evaluation with proper and validated questionnaires.
The research, thus, moves from the clinical evidence of the immune suppression due to GCs, trying to better understand the underlying mechanisms in patients exposed to high levels of GCs, using CS as a model. This will be the first study considering the PD-1 expressions on the PBMC, and cytokines concentration in patients with CS, evaluating also metabolic profile, prevalence and severity of infectious disease and quality of sleep.
In brief, identifying the mechanisms underlying GC immunosuppression would allow a better understanding of the signs and numerous complications associated with CS, a target use of GCs therapy in patients who can benefit from it, avoiding exposing others to the numerous side effects. Finally, results can help to optimize the use of ICI in cancer therapy.
The proposed research moves from the clinical evidence of the immune suppression due to GCs, trying to better understand the mechanisms that induce immune suppression in patients exposed to high levels of GCs using Cushing's Syndrome (CS) as a model. CS represents a peculiar and unique prototype of endogenous GCs hypersecretion.
This will be the first study considering the PD-1 expressions on the PBMC, focusing on NK cells, and cytokines (IL-12, IL-15 and IL-18) concentrations in patients with CS. The hypothesis is that the immune suppression due to GCs may be due to the increased expression of PD-1 on PBMC, and in particular on NK cells which can play a major role. Cytokines in high concentrations may contribute to this effect.
We will characterize the endocrine and immune profile of CS patients. Moreover, we will evaluate prevalence and severity of infectious disease in the context of immune suppression due to GCs. We will also consider quality of sleep and its dysfunctional parameters and the eventual correlation with the immune suppression in the context of CS patients.
Identifying the mechanisms underlying GC immunosuppression would allow a better understanding of the signs and numerous complications associated with CS. Furthermore, it would make possible the targeted use of GCs therapy in patients who can benefit from it, avoiding exposing others to the numerous side effects. We finally believe that this evaluation in the specific setting of CS can add important evidence to this complex topic which is still underexplored, also providing useful information to optimize the use of ICI in cancer therapy.