The hippocampus is subjected to diurnal/circadian rhythms on both the morphological and molecular levels. Certain aspects of cell proliferation in the adult hippocampus are regulated by melatonin and accompanied by apoptosis to ensure proper tissue maintenance and function. The present study investigated Zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis in the adult murine hippocampus and their regulation by melatonin receptor type1 and type2 (MT1/2)-mediated signaling. Adult melatonin-proficient C3H/HeN mice and melatonin-proficient (C3H/HeN) mice with targeted deletion of MT1/2 were adapted to a 12-h light, 12-h dark photoperiod and were sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 and activated caspase-3 in combination with different markers for the diverse cell types residing in the hippocampus served to identify and quantify proliferating and apoptotic cells in the hippocampal subregions. ZT-dependent changes in cell proliferation and apoptosis were found exclusively in the subgranular zone (SGZ) and granule cell layer (GCL) of melatonin-proficient mice with functional MT1/2. Cell proliferation in the SGZ showed ZT-dependent changes indicated by an increase of proliferating immature neurons during the dark phase of the 24-h light-dark cycle. Apoptosis showed ZT-dependent changes in the SGZ and GCL indicated by an increase of apoptotic immature neurons at ZT06 (SGZ) and a decrease of immature and mature neurons at ZT18 (GCL). Our results indicate that ZT-dependent changes in proliferation of immature neurons in the SGZ are counterbalanced by ZT-dependent changes in apoptosis of immature and mature neurons in the SGZ and GCL exclusively in mice with functional MT1/2. Therefore, MT1/2-mediated signaling appears to be crucial for generation and timing of ZT-dependent changes in cell proliferation and apoptosis and for differentiation of proliferating cells into neurons in the SGZ. © 2017 Wiley Periodicals, Inc.

Because of the particular anatomy of ovaries, which are in close contact with the adipocyte-rich omentum, ovarian cancer frequently presents itself with established metastasis-like disseminated tumor islets along the omentum. The tropism of ovarian cancer cells for fat is well described. Indeed, adipocyte-derived free fatty acids have been causatively linked to cancer cell proliferation and invasive properties. Obesity is additionally linked to increased risk of ovarian cancer onset and, in ovarian cancer patients, to worse outcome. However, there is to our knowledge no clear association between omentum-anchored dissemination and the anti-tumor immune response. Here we describe an unsuspected association between the presence peritoneal fat in ovarian tumors and massive tumor infiltration by T cells. Still, this massive T cell influx seems to fail in its anti-tumor activity since (1) tumor-infiltrating T cells seem to be hijacked away from tumor cells and accumulate around fatty areas and (2) tumor-infiltrating T cells display an exhausted phenotype. In this presentation, we also describe a new model of tissue culture of explants from primary human tumors that are treated with various drugs in an attempt to circumvent this fat-derived immune exhaustion and restore an efficient anti-tumor immune response. Citation Format: Meggy Suarez-Carmona, Anita Heinzelmann, Nektarios A. Valous, Mareike Hampel, Anna Berthel, Sarah Schott, Inka Zörnig, Dirk Jäger, Niels Halama. The fat in ovarian cancer: Immune-dependent tumor-promoting effects [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A102.

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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, Bénédicte 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.

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