Tumor Associated Macrophages (TAMs) a pivotal orchestrator in cancer-related inflammation and a new important target in cancer-therapy

Macrophages are pivotal orchestrators of tumor-promoting inflammation and promising targets for new anti-cancer therapies. To identify new molecular players underlying their pro-tumoral activities, we analyzed the phosphoproteoma of tumor associated macrophages (TAMs) isolated from murine fibrosarcoma. We identified the protein TRIM28, a pleiotropic molecule that is known to be involved in the dynamic organization of chromatin, and we characterized the signaling pathway driving its phosphorylation in response to inflammatory signals and its impact on LPS-induced gene expression. We explored in vivo the functional relevance of TRIM28 and found a significant reduction of colitis associated cancer lesions in mice lacking TRIM28 in intestinal epithelial cells. Single cell RNAseq analysis pointed out alterations of both immune and intestinal cell populations during the transition from colitis to cancer, that are dependent on TRIM28. Overall, these results identify TRIM28 as a new molecular target at the crossroads between inflammation and cancer. Beyond contributing to tumorigenesis, TAMs can profoundly affect the response to anti-cancer therapies. We investigated their impact on EPZ-6438, an inhibitor of the histone methyltransferase EZH2 that has recently entered in clinical trials due to the anti-proliferative effects shown on malignant pleural mesothelioma cells (MPM). We generated an MPM spheroid model that recapitulates in vitro, both monocyte recruitment in tumor and their functional differentiation towards a TAM-like phenotype (Mo-TAMs) capable of promoting tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with EPZ-6438 enhances both Mo-TAMs recruitment and pro-tumor phenotype expression, thereby limiting the anti-proliferative effects due to EZH2 inhibition in MPM cells. These findings indicate that strategies of TAM depletion should be combined with EPZ-6438 to improve the therapeutic efficacy of pharmacological EZH2 inhibition.