Combining epigenetic and macrophage reprogramming to boost anti-tumor immunity of malignant pleural mesothelioma

Background Malignant pleural mesothelioma (MPM), a highly aggressive thoracic cancer linked to asbestos exposure, is generally refractory to conventional therapies. Although immunotherapies targeting PD-1 and CTLA-4 have shown promise in treating MPM, most patients are resistant to treatment due to poor tumor immunogenicity and pronounced immunosuppressive microenvironment (TME). Thus, both predictive biomarkers and alternative therapies are urgently needed to improve MPM patient outcome. Hypothesis Besides its anti-antiproliferative effects on tumor cells, the inhibitor of histone methyltransferase enhancer of zeste homolog 2 (EZH2) tazemetostat affects TME composition. Our preliminary results using a 3D multicellular spheroid (MCS) model of human MPM indicate that macrophage depletion or M1-reprogramming can improve the anti-tumor effect of tazemetostat and boost anti-tumor immunity, thereby improving the efficacy of immune checkpoint blockades (ICBs). Thus, we hypothesize that low EZH2 activity and tumor associated macrophage (TAM) density are favorable predictors of ICB response. Furthermore, since preclinical studies indicate that (i) tazemetostat rescues cisplatin resistance in various cancer types, and that (ii) inflammatory myeloid cells enhance the cytotoxic effect of platinum compounds, we propose that the combination of EZH2 and M1-macrophage reprogramming can improve the efficacy of cisplatin/pemetrexed (CP), which is the standard-of-care treatment for epithelioid MPM. Aims To test these hypotheses, we will: 1)Assess the therapeutic efficacy of treatments with tazemetostat plus ICBs or CP combined with macrophage depletion or reprogramming in human and murine preclinical MPM models; 2)Determine markers of EZH2 activity and the frequency of immunosuppressive myeloid and anti-tumor T cells in association with MPM patient outcome and ICB response using human MPM biopsies. Experimental Design (WP1) In our human MCS model, we will assess the anti-cancer activity of tazemetostat combined with strategies aimed to deplete macrophages (CSFR1 inhibitor) or trigger their M1-reprogramming (STING agonist, GEM, EP2 and EP4 inhibitors) or effector functions (anti-CD47, anti-LILRB1). Additionally, we will determine the effect of CP in combination with tazemetostat alone or with the most effective approaches for boosting macrophage anti-tumor activity. (WP2) In murine orthotopic MPM models, we will assess the anti-tumor effect of either ICB or CP treatment combined with the strategies defined in WP1 by monitoring tumor burden, overall survival, and immune infiltrate. (WP3) In human MPM biopsies, we will analyze the expression of epigenetic markers of EZH2 activity as well as the frequency of myeloid and T cells according to outcome and ICB response. Expected Results We expect to identify new combination strategies triggering anti-tumor immunity in pre-clinical models and to validate the expression of therapeutic target in human MPM samples, thereby opening new therapeutic avenues for refractory MPM patients. Moreover, we will define epigenetic traits and myeloid cells in tumor and liquid biopsies as biomarkers to guide patient treatment selection. Impact On Cancer Our proposal aims to devise-in the short-term-novel immunotherapy strategies for personalized treatment of MPM patients based on drugs that have already been tested and approved for human use.