Abstract 370: Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia

Most people with advanced cancer exhibit cachexia, a syndrome of progressive weight loss that leads to the death of 20% of patients. The mechanisms underlying cachexia remain poorly understood and, as a result, no treatment has proven effective to date. Cachexia is characterized by systemic hyperinflammation, massive apoptotic cell death (“debris”), and skeletal muscle wasting. Here, we hypothesize that disrupted resolution of inflammation contributes to cancer cachexia, and pro-resolving lipid mediators, specifically novel specialized pro-resolving mediators (SPMs), could control cachexia. SPMs enhance resolution of inflammation by stimulating debris clearance, promoting tissue regeneration, and regulating major immune cell types. In testing our hypothesis, we profiled lipid mediators in a variety of metastatic cachexia models via metabololipidomics and investigated the changes of leukocytes, e.g., T lymphocyte, natural killer (NK), and macrophage cells, in various skeletal muscles (e.g., tibialis anterior and gastrocnemius). Dysregulation of SPMs was identified in different tissues in 5 cachexia models. The SPMs resolvin (RvD)2 and maresin (MaR)1 were reduced in the liver and spleen of colon cancer (CT26)-induced cachectic mice on day 35 post-tumor cell injection and RvD1, RvD2, lipoxin (LXA)4, and MaR1 were dysregulated in Lewis lung carcinoma (LLC)-induced cachectic mice on day 20. Chemotherapy was also found to dysregulate SPMs and induce cachexia in lymphoma (EL4) and ovarian cancer (ID8) mouse models. Ten days post-LLC tumor resection, the RvD1 receptor (ALX/FPR2) KO and RvE1 receptor (ChemR23/ERV) KO mice exhibited a 20-23% loss in body weight compared to WT mice. This shows that neutralizing the pro-resolving activity of RvD1 and RvE1 induces cancer cachexia. Moreover, RvD2 and PCTR (protectin conjugates in tissue regeneration)-2 prevented LLC- and B16F10 melanoma-induced cachexia at 15 ng/day. RvD4, RvD5, MCTR1, or MCTR2 inhibited inflammation-stimulated cytokine storm by counter-regulating the production of CCL3, CCL4, CXCL2, TNF-α, CCL2, G-CSF, and PAI-1. These results indicate that disrupted resolution of inflammation leads to the progression of cancer cachexia, and dysregulated SPMs are potential early markers for cachexia. This study provides a basis for the clinical translation of SPM-directed treatments as a new direction to potentially control cancer cachexia in humans. Citation Format: Ahmed Attaya, Victoria Haak, Abigail Kelly, Haixia Yang, Eva Rothenberger, Steven D. Freedman, Charles N. Serhan, Dipak Panigrahy. Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 370.