Multifaceted effects of obesity on cancer immunotherapies: Bridging preclinical models and clinical data

Potential roles of sex-linked differences in obesity and cancer immunotherapy: revisiting the obesity paradox

“…Care must be taken when making associations between obesity and ICI outcome, as there are limitations in modeling/studying, most notably a heavy reliance on BMI as a diagnostic tool and preclinical modeling that may not appropriately mirror human paradigms. Obesity has been linked with chronic inflammation, immune suppression, altered metabolism, and increased cancer incidence 12,27,74 . Additionally, obesity has been associated with increased T cell exhaustion and upregulation of inhibitory proteins including PD-1, LAG-3 and TIM-3 17,127 .…”

“…https://doi.org/10.1038/s44324-024-00007-4 diet (HFD) or a Western diet (characterized by high fat and high sugar), over an extended period of time, to induce weight gain and an overt obese phenotype. DIO models have gained traction, given their greater applicability to human obesity and lack of genetic abnormalities 27 . A notable limitation of these murine models is the lack of an equivalent metric to BMI, with mouse obesity often being characterized by a weight differential from controls, which in some models or strains of mice can be variable and, at times, arbitrary.…”

Suppressive effects of obesity on NK cells: is it time to incorporate obesity as a clinical variable for NK cell-based cancer immunotherapy regimens?

“…10 Obesity has been consistently implicated as a negative prognostic indicator regarding cancer incidence, progression, and clinical outcomes. 11 While BMI is often used as the primary tool for assessing obesity, it has been increasingly recognized that other parameters such as: hip to waist ratio, determination of lean muscle mass via imaging, and assessment of key metabolic parameters are more accurate parameters for prognostic purposes. 11 Obesity exerts marked immunological effects and is classically associated with a "metainflammatory" state due to increased pro-inflammatory cytokine responses affecting all tissues.…”

“…11 While BMI is often used as the primary tool for assessing obesity, it has been increasingly recognized that other parameters such as: hip to waist ratio, determination of lean muscle mass via imaging, and assessment of key metabolic parameters are more accurate parameters for prognostic purposes. 11 Obesity exerts marked immunological effects and is classically associated with a "metainflammatory" state due to increased pro-inflammatory cytokine responses affecting all tissues. 11 12 Obesity is also associated with an overall immunosuppressive phenotype resulting in: increased T-cell memory conversion and exhaustion, skewing to Th17 responses, increased regulatory T cells (Tregs), increased myeloid-derived suppressor cells, M1/M2 macrophage polarization, impaired primary antigen-specific responses, increased pro-inflammatory cytokine production, altered dendritic cell function, as well as impaired NK cell maturation and function.…”

“…11 12 Obesity is also associated with an overall immunosuppressive phenotype resulting in: increased T-cell memory conversion and exhaustion, skewing to Th17 responses, increased regulatory T cells (Tregs), increased myeloid-derived suppressor cells, M1/M2 macrophage polarization, impaired primary antigen-specific responses, increased pro-inflammatory cytokine production, altered dendritic cell function, as well as impaired NK cell maturation and function. 11 The causes of these immune effects in obesity are multifactorial and complex, with increased adiposity, alterations in hormones such as adipokines, leptin and insulin, increased fatty acids, and even alterations in the microbiome all likely playing roles depending on the immune cell type and location. 11 13 Many of these same pro-inflammatory immunosuppressive conditions likely directly fuel cancer growth and progression, and underpin the association between obesity and worse outcomes in many cancers.…”