Cancer-associated mesothelial cells drive immune escape and therapy resistance in ovarian cancer

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Background Cancer-associated mesothelial cells (CAMCs) are key modulators of the ovarian tumor microenvironment, contributing to tumor growth and immune evasion. Mesothelial cells (MCs) maintain peritoneal homeostasis and immune surveillance and represent the first point of contact during abdominal dissemination of ovarian cancers. Yet, their role in ovarian tumor immunity remains poorly understood. Methods Lineage tracing, 3D models, and spatial transcriptomic profiling were used to characterize CAMC origin, localization, and phenotypic transitions during ovarian cancer progression. Multiplex cytokine panels were used to define the cytokine profiles associated with MC transformation into CAMCs. Functional studies were conducted in syngeneic ovarian cancer mouse models to assess the impact of CAMCs on tumor growth and response to immunotherapy. In parallel, CAMC-driven changes in immune cell phenotype and functional state within the tumor microenvironment were characterized. Results We demonstrate that CAMCs originate from peritoneal MCs, populate the tumor surface, and progressively infiltrate the tumor core while undergoing a phenotypic transition toward a fibroblast-like phenotype. We characterize the function of an unrecognized CAMC signature marked by SERPINB2 + expression and a combination of markers absent in normal MCs. CAMC Serpinb2+ cells have reduced expression of pro-inflammatory cytokines (IL-2, IL-7, IL-12, IL-15) and increased expression of IL-10, TGFβ1, and CCL17 compared with normal MCs. Functionally, the presence of CAMC Serpinb2+ cells correlates with accelerated tumor growth, reduced CD4 + T and B cell infiltration, an expanded Treg population, and ultimately resistance to combination immunotherapy in a syngeneic mouse model of ovarian cancer. Conclusions These findings identify CAMCs as central regulators of immune suppression in ovarian cancer and reveal a distinct SERPINB2 + immunosuppressive CAMC state associated with tumor progression and immunotherapy resistance. Targeting CAMCs may represent a promising therapeutic strategy to restore antitumor immunity and improve responses to current ovarian cancer treatments and immunotherapies.

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