PMN-MDSC-derived Activin A mediates Cancer-associated cardiomyopathy 4132

Abstract Description Introduction Cachexia stands as a significant contributor to cancer-related death. Cachectic patients suffer from wasting of cardiac and skeletal muscles. We previously demonstrated the role of suppressive tumour-induced neutrophils in cardiac and skeletal muscle atrophy and dysfunction in mouse models. These cells were found to be a major source of activin A, a cytokine of the myostatin family. Methodology: Mice were injected with a murine Lewis Lung Carcinoma cell line and euthanized after 2 weeks to assess cachexia and immune cell activation. To elucidate the mechanistic contribution of Activin A-producing PMNs to cachexia, we utilized a myeloid (LysM Cre) and PMN (Ly6G Cre) -specific deletion of activin A. Results Myeloid and PMN-specific deletion of the Activin A gene protected against cardiac wasting; however, it did not impact the infiltration of these cells. Western blot confirmed Activin A to phosphorylate Smad2/3 in the heart. RNA seq analysis of muscle tissue in tumour-bearing mice revealed an upregulation of mitophagy and protein degradation markers and inhibition of oxidative phosphorylation. Knocking out Activin A gene in PMNs reversed these effects and guarded against muscle loss under tumour burden. Conclusions We demonstrate that PMNs produce activin A that induces cardiac dysfunction by triggering pathways of protein degradation and altering energy production. Funding Sources Canadian Institutes of Health Research grant# RES0052619 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)