Association of cell-free DNA (cfDNA) levels with myeloid-derived suppressor cells (MDSC) levels in blood of patients (pts) with muscle invasive (MI) and metastatic (met) bladder cancer (BC).

Abstract

4528 Background: cfDNA can be detected in healthy individuals but higher concentrations are present in pts with cancer. MDSC are immature immunosuppressive cells that can be mobilized from bone marrow by tumor-related factors. Higher blood MDSC levels have been associated with worse outcomes in pts with solid tumors including BC. We assessed correlations between cfDNA and MDSC levels in pts with MIBC and met BC. Methods: Peripheral blood from pts with MIBC and met BC was collected in Streck BCT tubes and processed to obtain cf nucleic acid extracts. Total cfDNA was determined by fluorimetry. Cell-free DNA fragment size was measured by Bioanalyzer DNA analysis; 100-400 bp fragments (mono- and di-nucleosomal fragments linked to granulocytic processing of apoptotic and necrotic tumor cells) were designated low molecular weight (LMW-frags). The % of MDSC (CD33+/HLADR-) and subtypes were measured. MDSC subtypes were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+) and uncommitted (UNC-MDSC: CD15-/CD14-). Spearman’s correlation test was used for analysis. Results: Blood from 37 pts (19% women, 40% never smokers) with MIBC or met BC was collected: 15 (41%) with MIBC and 22 (59%) with met BC at time of collection. There was a significantly positive correlation between total MDSC and cfDNA levels (r = 0.57, P = 0.0003). Among MDSC subtypes, there was a significantly positive correlation between PMN-MDSC and cfDNA levels (r = 0.61, P < 0.0001). The higher level of LMW-frags was significantly but moderately associated with higher total MDSC (r = 0.43, P 0.008) and PMN-MDSC (r = 0.41, P 0.01) levels. There was no significant correlation between cfDNA level and other MDSC subtypes. Conclusions: There was a positive correlation between total and PMN-MDSC with cfDNA levels in blood from pts with MIBC and met BC. That may suggest a putative role for MDSC in mediating cfDNA release into the circulation, consistent with prior reports of granulocyte-mediated ctDNA processing. Further studies need to identify mechanisms and implications of our findings and potential correlation with clinical outcomes.