Abstract A114: Omental fat in ovarian cancer induces metabolic and immune alterations

Abstract

Epithelial ovarian cancer (EOC) is an immunogenic tumor entity, as evidenced by multiple correlative studies indicating the impact of intraepithelial tumor-infiltrating T lymphocyte (TIL) density on patient outcome. Immunotherapy trials have generated modest results so far and chemotherapy remains standard of care. In this study, we focus on EOC metastases invading the omentum. Our aim is to characterize their immune landscape with the goal of identifying specific targetable characteristics of these metastases, which are the most prevalent and relate to high morbidity.We used a cohort of 120 ovarian cancer specimens for histologic analysis, cytokine, or metabolic profiling. Furthermore, we developed an EOC tissue explant culture model and treated whole-tissue explants with drugs before assessing immune cell density, distribution, and activation status. Finally, we cultured macrophages isolated from patient-derived ascites to study their response to various treatments.Samples were classified into omental metastases and primary tumors (based on the presence of fat on histologic sections). We observed that omental metastases are characterized by an inflamed microenvironment orchestrated by macrophages and are infiltrated by high amounts of TILs with low expression of activation markers, and a skewed localization around fat patches. These TILs express high amounts of the tumor-supporting CCL5 chemokine. Macrophages storing fatty acids in the form of big vacuoles were found in these fatty tumors as well. Targeting macrophages using the CCR5 inhibitor maraviroc in whole tissue explants effectively restored T-cell distribution across the tissue and slightly affected macrophage polarization specifically in fat-containing tumors. Inhibiting fatty acid import in macrophages more dramatically affected the cytokine landscape, also specifically in fat-containing tumors, and established a Th1-supporting environment permeable to T-cell expansion and activation. In brief, omental metastases are characterized by: (a) a smoldering inflammatory reaction and high macrophage density, (b) increased T-cell accumulation around fatty areas away from cancer cells, and (c) T-cell exhaustion accompanied by CCL5 expression. Treatment of EOC explants revealed that macrophages infiltrating omental metastases can be repolarized in situ, leading to TIL expansion and activation. Citation Format: Meggy Suarez-Carmona, Nektarios A. Valous, Pornpimol Charoentong, Jakob N. Kather, Mareike Hampel, Benedicte M.A. Lenoir, Dyke Ferber, Sarah Schott, Sabine Kess, Inka Zoernig, Dirk Jaeger, Niels Halama. Omental fat in ovarian cancer induces metabolic and immune alterations [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A114.