Ascites and Ovarian Cancer Ecosystems

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Summary

Ovarian malignancy (OM), an assertive gynecological neoplasm, typically ascertained through widespread metastasis and the presence of ascitic fluid, is herein elucidated through a solitary-cell panorama encompassing five pertinent neoplastic locales, notably including omental metastases and malignant ascites. The amassed data delineate latent functions of memory T cells, enriched within the ascitic milieu, serving as a reservoir for infiltrated fatigued CD8+ T cells and T helper 1-like cells. Additionally, tumor-concentrated macrophages evince a predilection for derivation from monocyte lineage, in contrast to their ascitic counterparts, which predominantly exhibit embryonic lineage. Furthermore, the profiling of MAIT cells and dendritic cells within the malignant ascites, coupled with two distinct endothelial subpopulations within primary tumors, emerges as a predictive tool for the efficacy of platinum-based chemotherapy. Collectively, this inquiry presents a comprehensive overview of the feminine malignant ascites microenvironment, furnishing invaluable discernments into its interplay with neoplastic tissues and potentially illuminating markers for therapeutic responsiveness assessment and resistance prognosis in OM.

Research Criteria

This study aims to provide a comprehensive landscape of the ovarian cancer ecosystem involving multiple clinical sites, reveal unique cellular dynamics, and identify potential predictive biomarkers related to treatment response. The integration of single-cell transcriptomics with T-cell receptor tracking and sampling multiple patient sites provides insights into ascites-tumor connections and cell heterogeneity in ovarian cancer.

Fig.1 Experimental design. (Zheng, 2023)

Sample Type

Human ovarian cancer tissues.

Result—Lineage Relationships among Different T Cell Subgroups within Tumors and Ascites

The authors scrutinized the variegated composition of T cell subpopulations in disparate sample locations, discovering that immunosuppressive T cells, notably exhausted T cells (Tex) and regulatory T cells (Treg), predominantly pervaded solid tumor tissues, in contrast to effector T cells (Teff) and memory T cells (Tcm/Tem) which were abundant in ascites. Despite the presence of tumor cells in all ascites samples, the ascites microenvironment did not exhibit the pronounced immunosuppressive state intrinsic to the tumor. Delving into the developmental interrelationship between T cell subpopulations in tumors and ascites, the authors amalgamated single-cell TCR sequencing data to discern a considerable degree of TCR sharing between tumor-infiltrating Tex cells and ascites-enriched CD8+GZMK+Tem cells. Intriguingly, the latter was found more inclined to share TCRs with Tex cells in metastatic sites than with those in primary sites, suggesting their capacity to infiltrate tumor tissues and metamorphose into Tex cells, considering the terminal differentiation and suboptimal tissue migration ability of Tex cells. A parallel phenomenon was observed among CD4+T cells, elucidating CD4+Tcm in ascites and CD4+CXCL13+Th1-like cells in tumors as likely precursors and derivatives, respectively. The authors concluded that memory T cells in ascites serve as a crucial supplement to terminally differentiated tumor-infiltrating T cells, accentuating the pivotal role of ascites in molding the tumor microenvironment.

Fig.2 CD4+ T cell characterization and dynamics in HGSOC. (Zheng, 2023)

Result—Different Functional Phenotypes and Developmental Origins of Macrophages in the Microenvironment of Ovarian Cancer Ascites and Tumor Tissues

In the intricate tumor immune microenvironment, tumor-associated macrophages (TAMs) serve a pivotal role in immune regulation. The authors, contemplating tissue origin characteristics, bifurcated macrophage subgroups into two primary categories: tumor-enriched macrophages (TeMac) and ascites-enriched macrophages (AeMac). An analysis revealed TeMac's elevated expression of cell factors like VEGFA, CCL3, and CXCL12, indicating potent T cell recruitment capability, whereas AeMac upregulated genes characteristic of resident tissue macrophages (RTM), including LYVE1 and CD163. Despite the liquid milieu of ascites, the authors delved into the origins of macrophages in tumors and ascites. Through a comparative analysis of RTM scores among macrophage subgroups, supplemented with the Ms4a3Cre-RosaTdT lineage-tracing mouse model, they discovered that while macrophages in ovarian cancer tumor tissues primarily originate from monocytes, a minor faction demonstrated strong RTM characteristics (M10). Conversely, RTM emerged as a crucial source and principal component of ascites macrophages. The authors further integrated an analysis of myeloid immune cell groups from colorectal and liver cancers, concluding that despite the marked heterogeneity among macrophage subgroups of varied cancers and tissue origins, the M08, M09, and M14 macrophage subgroups in ovarian cancer ascites closely aligned with the M-C6-MARCO subgroup in liver cancer ascites, underscoring the combined influence of microenvironment and developmental origins on macrophage functionality.

Fig.3 In HGSOC, tumor-enriched and ascites-enriched macrophages have two distinct functional states. (Zheng, 2023)

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Reference

1. Zheng, X.; et al. Single-cell analyses implicate ascites in remodeling the ecosystems of primary and metastatic tumors in ovarian cancer. Nature Cancer. 2023: 1-19.