Background: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms characterized by clonal proliferation of hematopoietic stem cells, recurrent genetic abnormalities, myelodysplasia, ineffective hematopoiesis, peripheral-blood cytopenia, and a high risk of evolution to acute myeloid leukemia (AML). Mounting evidence indicated that dysregulating immune checkpoint pathways are implicated in the pathogenesis of MDS. Soluble ICs (sICs) are soluble forms of ICs, which can be measured from circulation. In solid tumors, sICs have been identified with roles in predicting prognosis and mediating resistance to ICIs. However, in MDS, it is still unclear whether expression of sICs are dysregulating in this disease and already has a prognostic influence at the time of diagnosis.
Aims: Investigate the profile of sICs, cytokines which may mediate PD-1/PD-L1 expression, the expression levels of PD-1 on T cells in treatment-naïve MDS patients, and verify possible associations between these parameters with clinical characteristics and to test their value as prognostic factors.
Methods: Between June 2020 to April 2022, 79 patients newly diagnosed with de-nove MDS/sAML were enrolled in this prospective study and managed upon clinical prognostic risk assessment by Revised International Prognostic Scoring System (IPSS-R), 55 healthy donors (HD) were enrolled as control. Profile of sICs (sPD-1, sPD-L1, sCTLA-4, sLAG-3, sTIM-3, sGITR, sOX40, s4-1BB, sST-2) and cytokines (IFN-γ, IFN-α2, IL-2, IL-2α, IL-6, IL-7, IL-10, IL-15, IL-17, TNF-α) were tested by ELISA, and the expression levels of PD-1 on T cells (CD3+, CD4+, CD8+, DPT, DNT）were measured using flow cytometry (FCM).
Results: Plasm sPD-L1 levels were significantly elevated in de-nove MDS patients compared with healthy controls, while other sICs including sPD-1, sLAG-3, sGITR and s4-1BB levels were lower in patients. Significantly lower percentage of PD-1+ CD3+ cells, PD-1+ CD4+ cells, PD-1+ CD8+ cells were also observed in MDS patients than in controls. Positive correlation was observed between PD-1+ CD4+ T-cells and sPD-1 levels. Among clinico-pathological features, male patients and lower hemoglobin (＜80 g/L) significantly correlated to high sPD-L1 levels. In addition, levels of sPD-L1 were significantly higher in high-risk group than in low-risk group.
Cytokines, including which had been demonstrated roles in mediating upregulation of PD-1 on T cells (CD3+, CD4+, CD8+, DPT, DNT) were also analysis, and we found the levels of TNF-α were positively correlated with sPD-L1 and sST2. An optimal sPD-L1 cutoff value of 55.81 pg/mL was defined by ROC curves for newly diagnosed MDS patients. According to this cutoff value, patients with higher pretreatment sPD-L1 (>55.81 pg/mL) had worse OS of 6.97 months (95%CI 5.533-9.167, P = 0.006). A multivariate Cox regression model with forward stepwise likelihood ratio was performed. Transfusion dependency (HR 3.151, 95%CI 1.475-13.952, P = 0.008) and higher pretreatment sPD-L1 level (≥73.79 pg/ml, according to median expression levels in MDS patients) (HR 3.472, 95%CI 1.222-9.862, P = 0.039) was identified as negative independent prognostic factors for OS.
Summary/Conclusion: In conclusion, sPD-L1 was a negative independent prognostic factor for MDS patients at the time of diagnosis. High levels of sPD-L1 were presented in patients with lower hemoglobin and higher risk group, associating with disease progressing.
Keywords: Myelodysplastic syndrome, Immunosuppression, Progression