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Abstract Advanced stage high grade serous ovarian cancer (HGSC) metastasizes preferentially to the omentum, which is a well-vascularized fold of peritoneal tissue covered by mesothelial cells and a major site of intra-abdominal fat accumulation. We previously reported that HGSC cells interact with mesothelial cells in the visceral adipose tissue by downregulating omentin, a novel adipokine, to promote the invasive potential and proliferation of cancer cells in the omental tumor microenvironment (TME). In addition, omentin induces a local rapid metabolic coupling between ovarian cancer cells and neighboring adipocytes by upregulating GLUT4 in adipocytes, which subsequently deprives glucose in the omental TME and suppresses HGSC cell progression. Besides the crosstalk between cancer cells and neighboring adipocytes and mesothelial cells play a role in modulating the malignant phenotypes of HGSC cells, crosstalk between cancer cells and other stromal cell types particularly the immune cells such as macrophages and T cells may also play a role. Our preliminary data showed that mice treated with recombinant omentin had markedly increased in activated CD8+ T cell density in the omental TME compared to the untreated control, suggesting that mesothelial cell-derived omentin may enhance immune surveillance in the omental TME and subsequently suppress HGSC progression. Therefore, in this study, we aim at further investigating the roles of omentin in modulating the crosstalk between adipocytes and various immune cells to enhance the immune surveillance in the immunosuppressive omental TME. Since adipocyte is one of the major cell types in the omental TME, we focus on identifying secretory proteins that can be upregulated by omentin in mature adipocytes and have been shown to play a role in reprogramming the immunosuppressive TME. We found that TSG-6 was the top gene upregulated by omentin in adipocytes. Furthermore, we demonstrated that TSG-6 neutralizing antibody attenuated the omentin-mediated suppressive effect on ovarian cancer invasive potential and prevented the binding of regulatory T cells to endothelial cells mediated by CXCL12. We also found that recombinant TSG-6 protein attenuated the CXCL12-induced Ca2+ mobilization in ovarian cancer cells. These findings suggest that TSG-6 mediates the effect of omentin in alleviating immune escape in ovarian cancer by blocking pro-inflammatory CXCL12-mediated signaling events, which might attenuate regulatory T cell trafficking to the tumor tissue, subsequently enhance CD8+ T cell activity and eventually suppress the malignant phenotypes. In conclusion, based on the above findings, further studies to delineate the roles of omentin/TSG-6 axis in modulating immune surveillance in HGSC and to develop omentin as a chemopreventive and therapeutic agent in the treatment of HGSC to improve patients’ survival rates are warranted. Citation Format: Chi Lam Au Yeung, Kay-Pong Yip, Karen H Lu, Deepak Nagrath, Samuel C Mok. Omentin: A novel immune modulator in the pro-inflammatory omental microenvironment of high-grade serous ovarian cancer abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B067.
Yeung et al. (Mon,) studied this question.