Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade

Abstract

The recent successes of immunotherapy have shifted the paradigm in cancer treatment but since only a percentage of patients respond, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general, and in cancer immunotherapy, in particular, is poorly understood. Here we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. Strikingly however, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival following checkpoint blockade which directly targets some of the pathways activated in obesity.

Association of Systemic Inflammation Index and Body Mass Index with Survival in Patients with Renal Cell Cancer Treated with Nivolumab

“…Patient age and gender are arising as potential prognostic/ predictive factors for immunotherapy response. In melanoma, older patients' !60 years responded more efficiently to anti-PD-1 agents, and the ORR to these drugs increased with age (27). In RCC, elderly patients' !70 years were associated with increased ORR of nearly 30% higher than the nearly 20% reported in younger patients (820).…”

T Cell Dysfunction and Exhaustion in Cancer

“…Infiltrating T cells often co-express multiple inhibitory markers, and expression of the corresponding ligands is evident in tumor cells. In addition, factors beyond tumor genomics influence cancer development and therapeutic responses, including host factors such as the gastrointestinal (gut) microbiome and obesity (Gopalakrishnan et al, 2018;Popovic et al, 2018;Wang et al, 2019e). For example, the frequency of CD8 + TILs expressing PD-1and TIM3 is higher in the diet-induced obese mice (DIO) than that in control mice.…”

“…Anti-PD-1 monotherapy had minimal to no effect on control mice but significantly reduced tumor burden and significantly improved the survival of DIO mice. It remains to be clinically described whether the environment in the obese state results in greater T cell function once checkpoint blockade is applied (Wang et al, 2019e). More importantly, understanding the relationship between heterogeneous dysfunctional T cells and the TME may significantly impact on the success of therapies like checkpoint blockade and could lead to the production of more functional CAR-T cells.…”

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…234 Indeed, clinical reports show that obese or overweight patients have improved immunotherapy efficacy in metastatic melanoma, non-small cell lung cancer (NSCLC), and other cancers leading to increased overall survival and/ or progression-free survival with higher PD-L1 associated with better hazard ratios. [235][236][237][238][239][240] Proposed mechanisms of action include inflammatory cytokines and mediators such as C-reactive protein or leptin signaling to modulate the T cell repertoire. 238,[241][242][243][244][245] Specifically, patients treated with ICB had reduced risk of death by 3.6% with every point increase in BMI.…”

“…[235][236][237][238][239][240] Proposed mechanisms of action include inflammatory cytokines and mediators such as C-reactive protein or leptin signaling to modulate the T cell repertoire. 238,[241][242][243][244][245] Specifically, patients treated with ICB had reduced risk of death by 3.6% with every point increase in BMI. 237,246 While those studies find an obesity-ICB efficacy link regardless of sex for most survival measures, one study found the obesity-associated boost in ICB efficacy for males only.…”