Abstract 384: CD14+S100A9 high monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer

Abstract

Abstract Introduction: Myeloid-derived suppressor cells (MDSCs) are heterogeneous family of myeloid cells suppressing T cell immunity in tumor bearing hosts. We recently described an increased population of granulocyte-like CD11b+/CD14-/CD15+ MDSC in non-small cell lung cancer (NSCLC) patients. The role of CD11b+/CD14+ MDSC, being characterized as an inflammatory-type monocyte in mice, has not been well studied in human cancer. Methods: CD11b+/CD14- and CD11b+/CD14+ cells, determined and phenotyped by FACS analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naïve advanced NSCLC patients were correlated to clinical data. T cells activation in response to CD3/CD28 co-stimulation was determined by CFSE staining and ELISA analysis of IFN-γ. Cytokines and growth factors in the cultured supernatants were analyzed by ELISA. Results: NSCLC patients had significant higher ratio of CD11b+/CD14+ and CD11b+/CD14- cells than normal subjects. CD11b+/CD14+, but not CD11b+/CD11b- cells, correlated with poor performance and poor response to chemotherapy. Suppression of CD8+ and CD4+ T cells in NSCLC PBMCs was reversed by depleting either CD11b+ cells or CD14+ cells, an effect not seen in normal PBMCs. Both isolated CD11b+/CD14- and CD11b+/CD14+ cells suppressed CD8+ T cells proliferation and IFN-γ production in CD11b-depleted PBMC with equal ability. Enrichment of HLA-DR-/low cells decreased the suppressive ability of the CD14+ cells. CD11b+/CD14+ cells were monocyte-like expressing CD33+, CD15-/low, IL-4Rα+ and S100A9high and produced iNOS/arginase. The ratio of S100A9high cells positively correlated with the suppressive ability of the CD14+ cells and was associated with poor response to chemotherapy. CD11b+/CD14+ cell suppression of T cell proliferation was revered by the iNOS inhibitor aminoguanidine hydrochloride, the arginase inhibitor nor-NOHA, the STAT3 inhibitor AG490 and the blocking antibodies for IL-13, IL-4Rα+ and IL-10. CD11b+/CD14+ MDSCs secreted significant higher amounts of TNF-α, IL-8, IL-10, IL-13 and HGF than normal CD11b+/CD14+ cells. Conclusion: The CD11b+/CD14+ inflammatory monocyte in NSCLC patients is a distinct subset of MDSC with important clinical relevance, probably through secreting inflammatory cytokines and growth factors. These cells expressed IL-4Rα and high levels of S100A9. Among CD11b+/CD14+ monocytic MDSC, the expression of S100A9 protein seemd to be related to the immunosuppression activity and clinical response to chemotherapy. The role of S100A9 protein deserves further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 384. doi:1538-7445.AM2012-384