Abstract 2870: Inhibition of DNA methylation and histone deacetylation synergistically reprograms M2-polarized macrophages and inhibits tumor growth by upregulating miR-7083-5p

Reactivation of epigenetically suppressed miRs, in tumors, have become increasingly relevant in clinical practice. But less epigenetic studies have been performed on tumor associated M2 macrophages that plays a key role in the functional regulation of epithelial cancer development. In this study, we used 5-Aza-2’5’Aza-deoxycytidine (Aza) or decitabine (5-Aza) plus Trichostatin A (TSA) as epigenetic drugs to study the M2 macrophage modulation in the tumor microenvironment. Epigenetic therapy, not only modulated the M2 macrophages to a tumoricidal phenotype, but also strengthened the tumor immune surveillance and eventually attenuated tumor growth. In vitro studies on M2 macrophages, showed that these epigenetic modifiers, namely 5Aza+TSA, fine-tuned the M2 macrophages into a ‘no more tumor friendly’ phenotype. Using comparative miR profiling, we identified nearly 79 miRs that were upregulated in M2 macrophages after epigenetic drug treatment. Of all miRs, miR-7083-5p showed 32 fold upregulation in M2 after epigenetic therapy and csf2ra, a GM-CSF receptor that helps in IL3 and GM-CSF signaling to M2 polarization, and CD43,a leukocyte marker, were one two of the important genes targeted by this miR-7083-5p. Nevertheless, re-expression of miR-7083-5p in M2 Macrophages in vitro, modulated M2 Macrophage to an anti-tumor phenotype and 4T1 tumor tissues showed inversed correlation between the expression of miR-7083-5p and its target,csf2ra and CD43,implying the pathological relevance of targeting. Considering the vital role of M2-TAM in tumor growth and metastasis, epigenetic drug mediated reactivation of miRs in M2-TAM could act as a promising therapeutic approach in cancer treatment. Citation Format: Poongkavithai Vadevoo Sri Murugan, Gunassekaran Gowri Rangaswamy, Byungheon Lee. Inhibition of DNA methylation and histone deacetylation synergistically reprograms M2-polarized macrophages and inhibits tumor growth by upregulating miR-7083-5p [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2870.