Single-cell sequencing unveils key contributions of immune cell populations in cancer-associated adipose wasting

Adipose tissue loss seen with cancer-associated cachexia (CAC) may functionally drive cachexia development. Using single-cell transcriptomics, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction of white adipose tissues from patients with or without CAC. We report depot- and disease-specific clusters and developmental trajectories of adipose progenitors and immune cells. In adipose tissues with CAC, clear pro-inflammatory transitions were discovered in adipose progenitors, macrophages and CD⁸⁺ T cells, with dramatically remodeled cell interatome among these cells, implicating a synergistic effect in promoting tissue inflammation. Remarkably, activated CD⁸⁺ T cells contributed specifically to increased IFNG expression in adipose tissues from cachexia patients, and displayed a significant pro-catabolic effect on adipocytes in vitro; whereas macrophage depletion resulted in significantly rescued adipose catabolism and alleviated cachexia in a CAC animal model. Taken together, these results unveil causative mechanisms underlying the chronic inflammation and adipose wasting without loss of fat mass. However, studies suggested that fat loss may precede muscle loss in CAC development. For example, genetic studies using CAC animal models showed that inhibition of lipolysis in white adipose tissues (WATs) through genetic ablation of either PNP42 (encoding patatin-like phospholipase-domain-containing protein 2), or LIPE (encoding hormone-sensitive lipase), significantly ameliorated myocyte apoptosis and proteasomal muscle degradation. These animals retained normal adipose and gastrocneumius muscle mass. Another study revealed that secretion of parathyroid hormone-related protein (PTHrP) from Lewis lung carcinoma, which led to "browning" of white adipose cells, contributed to increased energy expenditure in CAC. Treatment to animals developed with cachexia using an anti-PTHrP antibody inhibited adipose browning and prevented loss of skeletal muscle mass. Some clinical observations also pointed out that the alteration of WAT may precede muscle wasting in some patients.