Visceral adiposity and systemic inflammation in the obesity paradox in patients with unresectable or metastatic melanoma undergoing immune checkpoint inhibitor therapy: a retrospective cohort study

Abstract

BackgroundThe obesity paradox is a topic of increasing interest in oncology and epidemiology research. Although this phenomenon has been observed in melanoma patients receiving immune checkpoint inhibitors, little is known about its mechanism. We aim to investigate the prognostic value of obesity and its association with adiposity and systemic inflammation.MethodsThis retrospective study evaluates the data of patients who received pembrolizumab or nivolumab for unresectable or metastatic melanoma between June 2015 and April 2021. The skeletal muscle index (SMI) and visceral fat index (VFI) (cm2/m2) were calculated by dividing the cross-sectional areas of skeletal muscle and visceral fat by height squared. The systemic immune-inflammation index (SII) was defined as the total peripheral platelet count×neutrophil/lymphocyte ratio. Cox proportional hazard regression analysis was conducted to determine the association with overall survival.ResultsWe analyzed 266 patients with a median age of 60 years (IQR 51–69 years; 135 men and 131 women). The protective effect of obesity was independent of covariates (HR 0.60; 95% CI 0.37 to 0.99; p=0.048), but disappeared after adjusting for VFI (HR 0.76; 95% CI 0.41 to 1.40; p=0.380) or SII (HR 0.71; 95% CI 0.42 to 1.18; p=0.186). An increase of 10 cm2/m2 in VFI was associated with longer overall survival after adjusting for covariates (HR 0.88; 95% CI 0.79 to 0.99; p=0.029). The prognostic value of VFI remained and predicted favorable overall survival after additional adjustment for SMI (HR 0.86; 95% CI 0.76 to 0.98; p=0.025), but disappeared with adjustment for SII (HR 0.92; 95% CI 0.82 to 1.03; p=0.142). An increase of 100×109/L in SII was associated with poor overall survival when adjusted for covariates (HR 1.08; 95% CI 1.05 to 1.11; p<0.001) or when additionally adjusted for VFI (HR 1.07; 95% CI 1.04 to 1.10; p<0.001).ConclusionsVisceral adiposity and systemic inflammation are significant prognostic factors in patients with unresectable or metastatic melanoma receiving immune checkpoint inhibitors. The prognostic impact of visceral adiposity is dependent on systemic inflammation status.

Obesity paradox in patients with non‐small cell lung cancer undergoing immune checkpoint inhibitor therapy

“…In line with this, a recent study comprising patients with various cancer types treated with immunotherapy found that a higher ratio of visceral fat to subcutaneous fat was associated with favourable OS 31 . Another study involving patients with advanced melanoma who received ICI therapy also reported a positive association between visceral adiposity and improved OS, which was interestingly influenced by systemic inflammation 13 . These findings supported the previous theory that the heightened efficacy of ICI therapy in individuals with obese BMI and more visceral adipose tissue might be related to their chronic inflammatory state and dysregulated immune response 29,32 …”

“…Specifically, some authors have proposed that the mechanism underlying the obesity paradox relies on the fact that patients with an obese BMI have higher levels of protective muscles, 8,9 which aligns with the widely recognized poor prognostic factor of sarcopenia 10,11 . Additionally, accumulating evidence indicates that adipose tissue may be a potential biomarker, as it has been positively associated with improved survival in patients with cancer 12,13 . However, it was unclear whether the obesity paradox was primarily influenced by specific components of body composition.…”

Do proton pump inhibitors alter the response to immune checkpoint inhibitors in cancer patients? A meta-analysis

“…In a 2022 retrospective study, Lee et al. showed similar results on OS for melanoma ( 83 ). In another study, Cortellini et al.…”

“…In 2018, McQuade et al showed a positive impact of high body mass index (BMI) on OS and PFS for metastatic melanoma patients treated by ICIs (82) but not for the chemotherapy group. In a 2022 retrospective study, Lee et al showed similar results on OS for melanoma (83). In another study, Cortellini et al (84) reported that PFS and OS were longer for patients with advanced cancers in BMI>25 group.…”

“…First, obesity may cause low systemic inflammation and impaired immune response, which could induce exhausted T-cell (which expressed PD-1) and lymphocytes dysfunction ( 85 ). Leptin is more secreted, which could increase PD-1 expression too ( 83 ). Second, gut microbiota is modified in obese patients.…”