Abstract 1990: Exploring the immune-metabolic mechanisms of adipose tissue in oesophageal adenocarcinoma
Authors: O'Connell Fiona , Mylod Eimear , Heeran Ailsing B. , Donlon Noel E. , Davern Maria , Butler Christine , Bhardwaj Anshul , Donohoe Claire , Ravi Narayanasamy , Renyolds John V. , Dunne Margaret R. , Roche Helen M. , O'Sullivan Jacintha 
Published: June 2022

Background: Oesophageal Adenocarcinoma (OAC) is the most strongly associated cancer with obesity. Approximately 75% of OAC patients are obese which results in chronic systemic low-grade inflammation, which is believed to drive carcinogenesis as well as influencing radiation treatment response. Adipose tissue is a regulatory organ with many downstream effects which are still not understood. This study aims to elucidate what influence adipose tissue metabolism and secretome have in treatment resistance and whether obesity alters this response.

Methods: Following patient consent, ex-vivo Visceral Adipose Tissue (VAT) explants were exposed to increasing doses of radiation with/without Palmitate and Oleate. Agilent Seahorse Xfe24 was used to measure oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in VAT explants and mitochondrial metabolic parameters in dendritic cells (DCs) following treatment with Adipose Conditioned Media (ACM). Levels of DC maturation following irradiated ACM exposure and Macrophage (Mɸ) polarisation following ACM or Tumour Conditioned Media (TCM) exposure were analyzed by flow cytometry. Irradiated ACM and TCM were analyzed via MSD 54plex ELISA to assess secreted factors on angiogenic, chemokine, cytokine, inflammatory, TH17 or vascular injury panels.

Results: VAT explant energy metabolism showed a significant increase for OCR and ECAR with obesity and increasing radiation exposure however OCR was significantly decreased following Palmitate treatment compared with untreated and Oleate treated adipose explants (p&lt;0.05). DCs treated with iACM showed decreased expression of CD11c, CD80, CD86, HLA-DR, CD40 and PD-L1 with increasing radiation in a dose-dependent manner and decreased HLA-DR and CD54 following ACM exposure from obese versus non-obese patients (p&lt;0.05). Mɸ showed increased expression of pro-inflammatory and anti-inflammatory markers following ACM exposure but following TCM exposure only anti-inflammatory markers were increased (p&lt;0.05). DCs showed altered Proton Leak, Basal and ATP linked respiration following exposure to ACM (p&lt;0.05). Altered secretion of proinflammatory mediators was observed from the obese adipose secretome compared with non-obese patients and with increasing radiation doses (p&lt;0.05).

Conclusion: We have demonstrated that obesity and increasing radiation doses can significantly alter the immune-metabolic influences of adipose tissue and further studies are profiling the lipidomic and metabolomic landscape of the adipose secretome. Alterations in the secretome of adipose tissue could potentiate the tumor microenvironment and deleteriously affect immune cell function therefore further interrogation is required to fully elucidate the influence adipose tissue may have in treatment response.

Citation Format: Fiona O'Connell, Eimear Mylod, Ailsing B. Heeran, Noel E. Donlon, Maria Davern, Christine Butler, Anshul Bhardwaj, Claire Donohoe, Narayanasamy Ravi, John V. Renyolds, Margaret R. Dunne, Helen M. Roche, Jacintha O'Sullivan. Exploring the immune-metabolic mechanisms of adipose tissue in oesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1990.