Supplementary Figures 1-8. Supplementary Fig. 1. CD11b+Gr1+ populations were isolated by FACS from spleens of tumor-bearing p120-/- and control mice. Supplementary Fig. 2. CD38 is expressed by the CD11b+Gr1+ population in a murine model of Barrett's Esophagus. Supplementary Fig. 3. The HNM007 tumors induce CD38 expression on MDSC population similarly to the autochthonous p120-/- tumors. Supplementary Fig. 4. Immunohistochemical analysis of HNM007 tumors co-injected with CD38High or CD38Low MDSCs. Supplementary Fig. 5. CD38high CD11b+Gr1+ cells produce higher levels of iNOS and pNFκB. Supplementary Fig.6. Network analysis of differentially regulated genes in CD38high and CD38low MDSCs shows upregulation of RB1 pathway. Supplementary Fig.7. Distribution of G-MDSC, M-MDSC and mature monocytes is perturbed in tumor-bearing Cd38-/- mice. Supplementary Fig. 8. CD38 is expressed on human MDSC-like cell population that is expanded in the peripheral blood of advanced-stage cancer patients.
ARTICLE ABSTRACT
Myeloid-derived suppressor cells (MDSC) are an immunosuppressive population of immature myeloid cells found in advanced-stage cancer patients and mouse tumor models. Production of inducible nitric oxide synthase (iNOS) and arginase, as well as other suppressive mechanisms, allows MDSCs to suppress T-cell–mediated tumor clearance and foster tumor progression. Using an unbiased global gene expression approach in conditional p120-catenin knockout mice (L2-cre;p120ctnf/f), a model of oral–esophageal cancer, we have identified CD38 as playing a vital role in MDSC biology, previously unknown. CD38 belongs to the ADP-ribosyl cyclase family and possesses both ectoenzyme and receptor functions. It has been described to function in lymphoid and early myeloid cell differentiation, cell activation, and neutrophil chemotaxis. We find that CD38 expression in MDSCs is evident in other mouse tumor models of esophageal carcinogenesis, and CD38high MDSCs are more immature than MDSCs lacking CD38 expression, suggesting a potential role for CD38 in the maturation halt found in MDSC populations. CD38high MDSCs also possess a greater capacity to suppress activated T cells, and promote tumor growth to a greater degree than CD38low MDSCs, likely as a result of increased iNOS production. In addition, we have identified novel tumor–derived factors, specifically IL6, IGFBP3, and CXCL16, which induce CD38 expression by MDSCs ex vivo. Finally, we have detected an expansion of CD38+ MDSCs in peripheral blood of advanced-stage cancer patients and validated targeting CD38 in vivo as a novel approach to cancer therapy. Cancer Res; 75(19); 4074–85. ©2015 AACR.
