Abstract 663: Resistin mediates the immunoediting activity exerted by primary human macrophages towards mesothelioma cells

Abstract Tumor-associated macrophages (TAM) are particularly abundant (i.e. 27% ± 9%) in the microenvironment of malignant pleural mesothelioma (MPM). These macrophages do not correspond to classical (M1) and alternatively-activated (M2) phenotypes but, instead, are shaped by local inflammatory mediators released in the pleura. We previously showed that, besides classical functions exerted by macrophages (i.e. phagocytosis, cytokine expression and antigen presentation), murine RAW264.7 cells are directly cytotoxic to MPM tumors (Hamaidia et al, JCI Insight 4:e128474). Upon direct cell-to-cell contact, RAW264.7 macrophages kill mesothelioma cells by a mechanism of oxeiptosis involving the enhancer of zeste homolog 2 (EZH2) methyltransferase. We have now investigated this immune-editing activity in human mesothelioma. We show that M1-activated primary macrophages are more cytotoxic for M14K cells than M2. The killing activity of M1 macrophages is dependent on NADPH oxidase activity and peroxynitrite levels. Mesothelioma cells and M2 macrophages interact through an inhibitory synapse characterized by engagement of the PD-1 receptor. Consistently, the immune-editing activity of M2 macrophages is partially restored in presence of neutralizing anti-PD1 antibody. Primary human macrophages cultured in presence of pleural effusions of MPM patients are less cytotoxic than M1 and are unable to inhibit tumor growth in mice. Macrophages differentiated in pleural effusions display a broad spectrum of cytotoxic activities (i.e. from complete inactivity to rates similar to those of M2). Luminex profiling of pleural fluids has identified a series of key mediators associated with the cytotoxic phenotype. The best correlation is obtained with resistin (RETN, FIZZ3, ADSF). Recombinant human resistin improves the killing activity of pleural effusion macrophages in cell culture. Gene transduction of RETN in RAW264.7 impairs growth of AB12 tumors in BALB/c mice. In conclusion, we have shown that resistin is the main factor that mediates immunoediting activity exerted by primary human macrophages towards mesothelioma cells, opening new prospects for therapeutic intervention. Citation Format: Malik Hamaidia, Majeed Jamakhani, Jean-Rock Jacques, Alexis Fontaine, Arnaud Scherpereel, Eric Wasielewski, Louis Renaud, Vincent Heinen, Bernard Duysinx, Luc Willems. Resistin mediates the immunoediting activity exerted by primary human macrophages towards mesothelioma cells [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 663.