Abstract 1515: Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer.

Abstract Myeloid-derived suppressor cells (MDSC) are one of the major factors negatively regulating immune responses in cancer and many other pathologic conditions. These cells consist of two distinct populations: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). PMN-MDSC is the predominant group of MDSC accumulated in cancer. Under physiologic conditions, the normal counterpart of M-MDSC - Ly6ChiLy6G- inflammatory monocytes (Mon) differentiate in periphery tissues to macrophages (MΦ) and dendritic cells (DCs). In contrast, a large proportion of M-MDSC, in tumor-bearing mice, acquired phenotypic, morphological and functional features of PMN-MDSC. In human, CD14+HLA-DR-/low M-MDSC from patients with multiple myeloma also differentiated into CD66b+ PMN-MDSC. This effect was caused by soluble tumor-derived factors and mediated by transcriptional silencing of the retinoblastoma (Rb) gene. M-MDSC had an amount of Rb1 similar to that in mature myeloid cells (PMN, DCs) while Rb1 was barely detectable in PMN-MDSC. Lack of Rb1 in mice with conditional deletion of the gene promoted an expansion of splenic CD11b+Ly6G+Ly6Clo cells, similar to the phenotype of PMN-MDSC in tumor-bearing mice. Moreover, immunogeneic EG7 tumor grew much faster in Rb1-KO mice than in Rb1-WT littermates. Mon from Rb1-KO mice acquired significantly increased proportion of PMN after in vitro culture compared to Rb1-WT Mon. In contrast, the overexpression of Rb1 substantially reduced the proportion of PMN-MDSC differentiated from M-MDSC. Histone deacetylase 2 (HDAC-2) was directly involved in down-regulation of Rb1 expression. Inhibition of HDAC in MDSC resulted in the increase in their Rb1 expression, abrogated differentiation of M-MDSC to PMN-MDSC, and restored M-MDSC differentiation towards DCs and MΦ. These results suggest that down-regulation of Rb by epigenetic modification plays a major role in accumulation of MDSC in cancer by regulating PMN-MDSC differentiation from M-MDSC. HDAC may be considered as potential targets for therapeutic regulation of MDSC in cancer. Citation Format: Je-In Youn, Vinit Kumar, Michelle Collazo, Dmitry I. Gabrilovich. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1515. doi:10.1158/1538-7445.AM2013-1515 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.