Type 2 immunity is maintained during cancer-associated adipose tissue wasting

Abstract

Cachexia is a systemic metabolic disorder characterized by loss of fat and muscle mass, which disproportionately impacts patients with gastrointestinal malignancies such as pancreatic cancer. While the immunologic shifts contributing to the development of other adipose tissue (AT) pathologies such as obesity have been well described, the immune microenvironment has not been studied in the context of cachexia. Here we assess the immune landscape of visceral AT (VAT) in the setting of pancreatic and colorectal cancers at the transcript, protein, and cellular levels. The cachexia inducing factor IL-6 is strongly elevated in the wasting VAT of cancer bearing mice, but the regulatory type 2 immune landscape which characterizes healthy VAT is maintained. Pathologic skewing toward Th1 and Th17 inflammation is absent. Similarly, the VAT of patients with colorectal cancer is characterized by a Th2 signature with abundant IL-33 and eotaxin-2, albeit also with high levels of IL-6. Our results suggest that wasting AT during the development of cachexia may not undergo drastic changes in immune composition like those seen in obese AT and provide a framework for further analyses of cancer associated cachexia.

Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia

“…Immune cells can secrete cytokines and regulate the microenvironment of tissues. Healthy adipose tissue is characterized by a regulatory type 2 immune signature which suppresses inflammation and maintains adipocyte function ( 96 ). On the other hand, gene expression analysis of WAT showed increased levels of activated M2 macrophage markers and unchanged M1 markers, along with a significant increase in the number of macrophages in cachectic mice ( 19 , 21 ).…”

Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back

“…Due to the increased utilization of energy conserving pathways, fasting has especially anti-inflammatory effects, while highly energy consuming pro-inflammatory responses are downregulated (139, 143). Consistent with this, Lenehan et al found a decrease especially of Th1 and Th17 inflammation in wasting AT of tumor-bearing mice, while the Th2 response were maintained (144). Collectively, fasting has a supporting effect on Th2 responses, while the more energy consuming type 1 inflammatory responses are inhibited.…”

“…In the absence of glucose, activation of Th cells via Glut1 is impaired ( 8 ), but whether this also impairs Th2 cell function, which seems to be intact although glycolysis cannot be used ( 213 ), remains to be determined. Interestingly, a recent study showed that during cancer-associated adipose tissue wasting the Th2-environment in adipose tissue is maintained both in mice and humans ( 144 ).…”

Harnessing immunometabolism for cardiovascular health and cancer therapy

“…In this issue, Lenehan et al . shed light on the critical role of adipose tissue in regard to immune cell function, while providing a framework for future cancer therapy research [ 14 ]. They show the absence of a shift toward Th1 and Th17 inflammation and a maintained regulatory type-2 immunity in the adipose tissue of mice with cachexia.…”