Immune and metabolic profile in acromegalic patients and the impact of the current medical treatment. Results from the PROMISE study

Introduction: Acromegaly is associated with several comorbidities, mainly cardiovascular, respiratory and metabolic diseases, with an increase in the last years of cancer as main cause of mortality. Conversely, little is known about the immune function in acromegaly, even if GH/IGF1 axis has long been supposed to play a role in immune modulation, mainly by affecting lymphocytes and monocytes. We aimed to evaluate the peripheral blood mononuclear cells (PBMCs) subpopulations in acromegalic patients (ACRO) in comparison with controls (CTRLs) and to investigate the impact of disease control and different medical treatments on PBMCs, metabolism and body composition. Material and Methods: This is an observational, prospective, single site, pilot study (NCT05069324). Twenty-nine patients (16 M and 13 F, mean age 51.3  15.6 years) with an active disease and 25 sex and age-matched healthy volunteers entered the study according to inclusion criteria. Twenty-five acromegalic patients underwent neurosurgery, 15 were on SSA treatment, and 10 patients on PEG (monotherapy or combined with SSA). Six patients with uncontrolled disease (IGF1  1.2 x ULN) on SSA treatment changed therapy (add or switch to PEG) and were evaluated after 8 weeks from the treatment change together with another group of 8 patients with stable disease. Anthropometric, metabolic and hormonal parameters were recorded along with full quantification of PBMCs evaluated by flow cytometry. Data are expressed as means  SD or median (IQR) and statistical analysis was performed with parametric and non-parametric tests, as appropriate. Results: Immune cell profiling revealed in ACRO compared to CTRLs decreased monocytes with a higher proportion of non-classical and a lower proportion of intermediate subset. Moreover, ACRO had lower NK cells and CD16high NK with an increased proportion of the more naturally cytotoxic subset (CD56dim) and a decreased proportion of the NK cells more responsible of cytokine production (CD56bright), without changes in T and B-lymphocytes. In ACRO group no differences were found according to disease control and medical treatment. Conversely, in treated acromegalic patients body composition parameters were similar to CTRLs, with a higher fat mass, particularly localized at trunk, in PEG treated patients compared to SSA treatment. The introduction of PEG, in comparison with the stable treatment, improved after 8 weeks glycaemia and influenced the immune cells redistribution by increasing the proportion of non-classical monocytes and CD56bright NK cells, without body composition changes. Discussion: To the best of our knowledge, this study demonstrated for the first time that acromegalic patients showed an immunological fingerprint, characterised by decreased monocytes and NK cells and by an imbalance of immune innate cells subset, supporting the role of GH/IGF1 axis in immune system modulation. These results could represent the background for further studies, particularly considering the relationship between immune function and cancer and the higher cancer risk reported in acromegaly. The treatment change (add or switch to PEG) may influence immune cells redistribution, without body composition effects, supporting a potential role of PEG in immune regulation. However, further studies are needed to confirm these data and to better clarify the underlying mechanisms and their potential clinical implications.