Senectus Ipsa Morbus Est? How to Distinguish Inflammaging from Inflammation of Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasia typical of the elderly. MDS patients are stratified according to IPSS-R score into lower- (LR) and higher– (HR) risk forms correlating with the probability of disease progression and length of survival. LR-MDS patients and the healthy elderly population (HC) share some biological characteristics, such as clonal hematopoiesis and dysregulated inflammatory profile. HCs are characterized by a chronic inflammatory state (named inflamm-aging), and a pro-inflammatory state has also been described in MDS patients. Given this background, we compared pro-inflammatory cytokines in serum of LR-MDS patients with these found in serum of age-matched HC. Results were integrated into an artificial intelligence (AI) algorithm to integrate clinical features and create a model to discriminate MDS patients from age-matched HC subjects. Compared with HC donors, LR-MDS patients were characterized by high levels of IL-1β, TNFR1, IL- 15 and IL-8 (MDS-Cyt cocktail) and low concentration of CCL2, CXCL4, CXCL7 and IL-7 (HC-Cyt cocktail). Despite the limited number of cases, the integration of cytokines data with clinical information into an AI model allowed us to develop a system able to distinguish the two groups with a good accuracy. We also went more in depth in granularity of stratification. Given the physiological sex-based diversity in the inflammatory response, sex-stratification revealed that males with LR-MDS presented high IL-6 levels. IL-6 production depends on estrogen levels and is physiologically higher in females; thus, our observation suggests that the MDS status alters the sex-dependent IL-6 expression. To assess whether inflammation in LR-MDS is a consequence of the disease or of aging, we evaluated the level of cytokines in “young” patients and “young” HC (i.e. <60 years). We observed that young patients have a specific age-independent cytokine profile, characterized by lower levels of CCL2 and CXCL4, similar to more aged LR-MDS cases. Finally, we tested in vitro the effect of cytokines cocktails typical of MDS and HC respectively on T-cells expansion and polarization. We noticed that CD8+ cells are largely expanded in MDS and only 1% of CD4+ are Tregs. Our in vitro experiments in HC showed that MDS-Cyt induce a similar expansion of CD8+ cells, but it also drives the expansion of 3 Tregs, probably to compensate CD8+ activity. We hypothesize that LR-MDS Tregs have intrinsic defects that could prevent CD8+ activation. However, functional studies are ongoing to confirm this hypothesis. In conclusion, our main finding is that the inflammatory profile of LR-MDS patients is characterized by an over production of pro-inflammatory cytokines and a reduction of chemokines concentration. We showed that these two conditions could lead to an altered T- cell function, promoting a compromised Tregs function and subsequent accumulation of CD8+ cells, phenomenon that could play an important role in LR- MDS clinical manifestations.