Dissecting the role of myeloid cells in cachectic white adipose tissues through a multilayered approach

Myeloid cells are key regulators of several physiopathological conditions. In detail, monocytes and macrophages (MM) play a pivotal role in homeostatic immune response acting as antigen-presenting, metabolic-supporting and tissue-healing pleiotropic cells. In individuals affected by cancer-associated cachexia (CAC) it has been observed a weakening (if not a failure) of adipose tissue MM commitment. White adipose tissue wasting is the primary cause of weight loss in CAC patients, in which there is a significant perturbation of tissue homeostasis and loss in immune cells crosstalk of both visceral (vWAT) and subcutaneous (sWAT) depots. Although CAC is widely studied, little is known about the role of MM in adipose wasting. To dissect the involvement of immune cells in cachectic adipose tissue decay, we performed a comprehensive single-cell RNAseq analysis of publicly-available vWAT and sWAT datasets of gastric cancer patients. First of all, we analyzed cell communities ratio: in both cachectic samples there was an expansion of lymphatic lineage. The largest increase was observed in vWAT B-cells but it is also noticeable in NK and T-CD8+ cytotoxic cells in either vWAT and sWAT. Conversely, MM nearly halved in both cachectic adipose tissues. We also spotted a defective myeloid-lymphoid crosstalk characterized by reduced communication pathways. To confirm this depletion, we performed a multiplex spatial confocal microscopy of cachectic mouse model that showed a poor recruitment of adipose macrophages. These results led us to further inspect the phenotype of such cells. As expected, MM of cachectic adipose tissues exhibited a chronic inflammatory polarization in both white adipose depots. Notably, while sWAT MM exhibited reduced metabolism, cachectic vWAT macrophages showed a significant increase in terms related to glycolysis, TCA-cycle, and oxidative phosphorylation. Next, we focused on MM’s mitochondrial activities and we found a significative enrichment in every mitochondrial-related category in vWAT MM. This analysis also revealed potential effectors like choline and cholesterol as promising targets to improve our understanding of adipose wasting progression. In brief, we explored elusive MM role in CAC through a parallel dry and wet approach, shedding light on unexplored mechanisms involved in adipose tissue pathological remodeling.