Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies.

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes’ recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.

Background: Long-term immunosuppressive therapy typically increases the risk of viral infection, yet during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, inflammatory bowel disease (IBD) patients showed reduced severe coronavirus disease 2019 (COVID-19) susceptibility. This suggests potential overlapping molecular mechanisms between IBD and COVID-19 that warrant investigation. Methods: From April 2020 to April 2022, we enrolled 363 IBD patients and 146 healthy donors. Serum samples were analyzed by enzyme-linked immunoadsorption assay to determine the presence of anti-SARS-CoV-2 antibodies and to measure concentrations of the host-soluble factors sACE2 and mannose-binding lectin (MBL), which have SARS-CoV-2 neutralizing activity. Furthermore, colonic mucosa biopsies were analyzed by real-time PCR to confirm the upregulation of MBL2 as well as to assess the expression of genes encoding SARS-CoV-2 entry molecules (ie, ACE2, TMPRSS2, TMPRSS4, ADAM17, AGTR1). Results: Intestinal mucosa expression of ACE2, TMPRSS2, and TMPRSS4 genes was significantly lower in IBD than in healthy individuals, regardless of the type of medication, while ADAM17 and AGT1R were similar across groups. Serum sACE2 levels changed minimally, whereas circulating MBL levels were significantly higher in CD and somewhat elevated in UC patients versus controls. Parallel trends in MBL2 gene expression were observed in IBD patients’ intestinal mucosa. Conclusions: Overall, our study indicates that the presence of higher basal circulating levels of MBL in CD patients and the decreased intestinal mucosa expression of the SARS-CoV-2 receptor ACE2 and the host cell priming proteases TMPRSS2 and TMPRSS4 in both CD and UC patients may reduce COVID-19 risk, underscoring the potential protective role of these biomarkers in IBD populations against SARS-CoV-2 infection.