Soluble PD-L1 Predict Poor Outcome and Disease Progression in Patients with De Novo Myelodysplastic Syndrome

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 indicates that dysregulating immune checkpoint pathways are implicated in the pathogenesis of MDS, which thus promoting a number of trials employing immune checkpoints inhibitors (ICIs) in different settings. 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 sICs levels are dysregulating in this disease and already has a prognostic influence at the time of diagnosis.

Method: Seventy-nine adult patients with untreated de novo MDS were enrolled in this prospective study and managed upon clinical prognostic risk assessment by Revised International Prognostic Scoring System (IPSS-R), 10 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). Follow-up time ended on June 21, 2022.

Result: MDS patients showed significant higher levels of sPD-1 and sPD-L1 (P＜0.01). Patients with high pretreatment sPD-L1 (>73.79 pg/mL) and high percent of PD-1⁺CD8⁺T cells (>7.3%) had worse OS (P < 0.05). Using a multivariate cox regression model adjusting established prognostic factors, including IPSS-R and transfusion dependency, high pretreatment sPD-L1 level was retained as a negative independent prognostic factor for OS (HR 3.151, 95%CI 1.061-9.364, P = 0.039). Moreover, to explore the roles of the PD-1/PD-L1 pathway in the pathogenesis of MDS, we examined the correlations between sPD-1, sPD-L1 and percent of PD-1⁺CD8⁺T cells and parameters associating with disease progression (Table. 1). Among clinico-pathological features, male patients showed higher levels of sPD-L1 and percent of PD-1⁺CD8⁺T cells, lower hemoglobin (＜80 g/L) significantly correlated to high sPD-L1 levels. In addition, in low- and very low- risk group according to IPSS-R, levels of sPD-L1 were significantly lower than intermediate-, high- and very high- risk group. Furthermore, in previous studies, it was reported that mPD-1/mPD-L1 can be induced by multiple inflammatory cytokines in cancer, including IFN-γ, IFN-α2, IL-2, IL-2α, IL-6, IL-7, IL-10, IL-15, IL-17, TNF-α, and we further tested them in our study. Correlation analysis showed that significant correlations were observed among different sICs as well as cytokines (Figure. 1). In addition, a positive correlation was found between TNF-α and sICs, including sPD-1, sPD-L1 and sST2 (P < 0.05).

Conclusions: 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.

No relevant conflicts of interest to declare.