Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and β1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting.
New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4-1BB (MBBz) CAR T cells induced long-term remission in some SKOV3-bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG3 in an antigendependent manner while MSLN þ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating that coin-hibitory pathways impede CAR T-cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z-and MBBz-treated mice characterized by elevated T-cell secreted factors that had increased survival, higher CD8 þ T-cell tumor infiltration, less exhausted CAR T-cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer.Significance: These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.
Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments.
Purpose: Uterine sarcomas are rare but deadly malignancies without effective treatment. The goal of this study was to characterize and identify potential mechanisms underlying observed variations in the immune microenvironment of different sarcoma subtypes, using integrated clinicopathological and molecular methods. Experimental design: Fifty-eight cases of uterine sarcoma with full clinicopathological annotation were analyzed for their immune landscape in the tumor microenvironment, gene, and protein expression. Cases included leiomyosarcoma (LMS; n=13), low-grade endometrial stromal sarcoma (ESS; n=16), undifferentiated uterine sarcoma (UUS; n=26), and YWHAE-FAM22 translocation-bearing ESS (YFAM; n=3). Image analysis was used to quantify immune cells and immune regulatory proteins. Gene ontology and network enrichment analysis of matching transcriptomic data was used to relate over- and under expressed genes to pathways and further to the immune phenotype and clinicopathological findings. Results: Immune cell characterization revealed overall prevalence of regulatory T cells and the pro-tumor M2-like macrophages. Cytotoxic T cells were only found in ESS and UUS tumors. Expression of immune regulatory proteins was heterogeneous, with PD-L1 being undetectable. Hierarchical clustering of patients showed four immune signatures independent of tumor type, where infiltration of non-exhausted FOXP3+ cells and M1-like macrophages were associated with greater overall survival. High CD8+/FOXP3+ ratio in UUS and ESS was associated with poor survival and upregulation of extracellular matrix (ECM)-related genes and proteins and YAP nuclear localization. Conclusions: Uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type. This study suggests that the ECM is a potential regulator of the immune microenvironment in uterine sarcomas.
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