Obesity and adipose tissue impact on T-cell response and cancer immune checkpoint blockade therapy

Abstract

Many different types of cancer are now well-known to have increased occurrence or severity in individuals with obesity. The influence of obesity on cancer and the immune cells in the tumor microenvironment has been thought to be a pleiotropic effect. As key endocrine and immune organs, the highly plastic adipose tissues play crucial roles in obesity pathophysiology, as they show alterations according to environmental cues. Adipose tissues of lean subjects present mostly anti-inflammatory cells that are crucial in tissue remodeling, favoring uncoupling protein 1 expression and non-shivering thermogenesis. Oppositely, obese adipose tissues display massive proinflammatory immune cell infiltration, dying adipocytes, and enhanced crown-like structure formation. In this review, we discuss how obesity can lead to derangements and dysfunctions in antitumor CD8+ T lymphocytes dysfunction. Moreover, we explain how obesity can affect the efficiency of cancer immunotherapy, depicting the mechanisms involved in this process. Cancer immunotherapy management includes monoclonal antibodies targeting the immune checkpoint blockade. Exhausted CD8+ T lymphocytes show elevated PD-1 expression and highly glycolytic tumors tend to show a good response to anti-PD-1/PD-L1 immunotherapy. Although obesity is a risk factor for the development of several neoplasms and is linked with increased tumor growth and aggressiveness, obesity is also related to improved response to cancer immunotherapy, a phenomenon called the obesity paradox. However, patients affected by obesity present higher incidences of adverse events related to this therapy. These limitations highlight the necessity of a deeper investigation of factors that influence the obesity paradox to improve the application of these therapies.

Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis—A Narrative Review

“…IL-33 binds to IL-33 receptors on Treg cells and, together with PPAR- γ , promotes a Treg signature and immune and metabolic homeostasis. A Treg signature in lean SAT promotes non-shivering thermogenesis via increased UCP-1 and beigeing of WAT [ 113 ].…”

“…Obesity results in the phosphorylation of PPAR- γ and the disappearance of Tregs and the suppression of adipogenesis in VAT [ 113 ]. There is a transition from the M2 to the M1-like macrophage phenotype in the ATM of obese individuals, which is mediated by adipocyte exosomes, NF- κ B, cyclooxygenase (COX)-2, Toll-like receptor (TLR) and Notch signalling pathways [ 73 , 109 ].…”

“…Obesity results in the phosphorylation of PPAR-γ and the disappearance of Tregs and the suppression of adipogenesis in VAT [113]. There is a transition from the M2 to the M1-like macrophage phenotype in the ATM of obese individuals, which is…”

Obesity and lung cancer – is programmed death ligand-1 (PD-1L) expression a connection?

“…Individual meta-analyses confirmed that obesity is an independent risk factor worsening both the morbidity and severity of lung cancer [ 2 , 3 ]. On the other hand, obese patients respond much better to immunotherapy based on immune checkpoint inhibitors, which is another example of the obesity paradox [ 4 ]. According to the presented thesis, the relationship between obesity and lung cancer immunology seems unclear.…”

“…Obesity is an independent risk factor for lung cancer development and is associated with increased tumor growth and aggressiveness. On the other hand, obesity is associated with improved response to cancer immunotherapy [ 4 ]. This result leads to the hypothesis that obese lung cancer patients should have a higher level of PD-1L expression compared to normal-weight patients.…”