http://manuscript.elsevier.com/S0169409X22001326/pdf/S0169409X22001326.pdf

Drug delivery for metabolism targeted cancer immunotherapy.

Contrary to the "obesity paradox," which arises from retrospective studies relying on body mass index to define obesity, epidemiologic evidence suggests central or visceral obesity is associated with a higher risk for the development of lung cancer. About 60% of individuals at high risk for developing lung cancer or those already with early-stage disease are either overweight or obese. Findings from resected patient tumors and mouse lung tumor models show obesity dampens immune activity in the tumor microenvironment (TME) encouraging disease progression. In line with this, we have observed a marked, obesity-specific enhancement in the presence and phenotype of immunosuppressive regulatory T (Treg) cells in murine tumors as well as the airways of both humans and mice. Leveraging direct metabolomic measurements and robust inferred analyses from RNA-sequencing data, we here demonstrate for the first time that visceral adiposity alters the lung microenvironment via dysregulated acetyl-CoA metabolism in a direction that facilitates immune suppression and lung carcinogenesis. 

/pdf/altered-acetyl-coa-metabolism-presents-a-new-potential-13liodd2.pdf

Altered acetyl-CoA metabolism presents a new potential immunotherapy target in the obese lung microenvironment

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause–effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.

/pdf/obesity-the-adipose-organ-and-cancer-in-humans-association-2tuu51wx.pdf

Obesity, the Adipose Organ and Cancer in Humans: Association or Causation?

Disruption of metabolic homeostasis at the organismal level can cause metabolic syndrome associated with obesity. The role of adipose tissue in cancer has been investigated over the last several decades with many studies implicating obesity as a risk factor for the development of cancer. Adipose tissue contains a diverse array of immune cell populations that promote metabolic homeostasis through a tightly controlled balance of pro- and anti-inflammatory signals. During obesity, pro-inflammatory cell types infiltrate and expand within the adipose tissue, exacerbating metabolic dysfunction. Some studies have now shown that the intracellular metabolism of immune cells is also deregulated by the lipid-rich environment in obesity. What is not fully understood, is how this may influence cancer progression, metastasis, and anti-tumor immunity. This review seeks to highlight our current understanding of the effect of adipose tissue on immune cell function and discuss how recent results offer new insight into the role that adipose tissue plays in cancer progression and anti-tumor immunity.

https://www.mdpi.com/2072-6694/13/13/3327/pdf

Francesca Limbeck

Papers

Instruction of Immunometabolism by Adipose Tissue: Implications for Cancer Progression