Cutting Edge: Elevated Leptin during Diet-Induced Obesity Reduces the Efficacy of Tumor Immunotherapy

Abstract

Various malignancies are reproducibly cured in mouse models, but most cancer immunotherapies show objective responses in a fraction of treated patients. One reason for this disconnect may be the use of young, lean mice lacking immune-altering comorbidities present in cancer patients. Although many cancer patients are overweight or obese, the effect of obesity on antitumor immunity is understudied in preclinical tumor models. We examined the effect of obesity on two immunotherapeutic models: systemic anti-CTLA-4 mAb and intratumoral delivery of a TRAIL-encoding adenovirus plus CpG. Both therapies were effective in lean mice, but neither provided a survival benefit to diet-induced obese BALB/c mice. Interestingly, tumor-bearing leptin-deficient () obese BALB/c mice did respond to treatment. Moreover, reducing systemic leptin with soluble leptin receptor:Fc restored the antitumor response in diet-induced obese mice. These data demonstrate the potential of targeting leptin to improve tumor immunotherapy when immune-modulating comorbidities are present.

The effects of age and systemic metabolism on anti-tumor T cell responses

“…One potential explanation for this discrepancy is that leptin may have different effects in the context of lean compared to obese organisms due to chronic exposure to elevated leptin levels with obesity. This hypothesis is supported by the observations that intratumoral leptin delivery provides no benefit in obese mice, in contrast to controls ( Rivadeneira et al, 2019 ), and that neutralization of leptin improves immunotherapy responsiveness in mice with diet-induced obesity ( Murphy et al, 2018 ). Further supporting the notion that leptin may reduce CD8 + T cell anti-tumor function in the context of obesity, a recent study found that leptin contributes to CD8 + tumor-infiltrating lymphocyte (TIL) dysfunction in a spontaneous breast cancer model ( Zhang et al, 2020 ).…”

“…Surprisingly, although obesity reduces the anti-tumor immune response, the efficacy of ICB cancer immunotherapy is enhanced in both animal models and human obesity in multiple cancer types ( McQuade et al, 2018 ; Wang et al, 2019 ; Xu et al, 2019 ; Figure 5 ). However, not all studies have found enhanced efficacy of ICB immunotherapy in mice with diet-induced obesity ( Murphy et al, 2018 ). This may be explained by several differences, including the mouse strain (BALB/c versus C57/BL6), cancer model (renal cell carcinoma versus melanoma and lung carcinoma models) and modalities of immunotherapy (anti-CTLA-4 combined with other immunostimulants versus anti-PD-1) ( Murphy et al, 2018 ; Wang et al, 2019 ).…”

“…However, not all studies have found enhanced efficacy of ICB immunotherapy in mice with diet-induced obesity ( Murphy et al, 2018 ). This may be explained by several differences, including the mouse strain (BALB/c versus C57/BL6), cancer model (renal cell carcinoma versus melanoma and lung carcinoma models) and modalities of immunotherapy (anti-CTLA-4 combined with other immunostimulants versus anti-PD-1) ( Murphy et al, 2018 ; Wang et al, 2019 ). The discrepancy in results obtained with these different animal models correlates with human data, where obesity improves the efficacy of ICB in patients with melanoma and non-small cell lung cancer, but not renal cell carcinoma ( Xu et al, 2019 ).…”

Obesity and the Impact on Cutaneous Melanoma: Friend or Foe?

“…Increased leptin in the obese mice was implicated in mediating the PD-1 expression and T cell exhausted phenotype [21]. In contrast, treatment response to CTLA-4 blockade was not improved in diet-induced obese mice, however when leptin was neutralized in this model an increase in the co-stimulatory molecule CD86 was observed as was the response to anti-CTLA therapy [79]. In both models, leptin is implicated in inducing an immunosuppressive microenvironment by increasing PD-1 expression and decreasing immune-stimulatory molecules.…”

“…Obesity not only induces an increase in tumor infiltration of MDSCs but also MDSC expression of PD-L1 thereby inhibiting anti-tumor responses and promoting tumor growth and metastasis [77]. In a preclinical melanoma model diet induced obesity led to a leptin-dependent decrease in functional DCs and tumor infiltrating CD8+ T cells indicating impairment of an anti-tumor response [79]. A recent study in a mouse melanoma model demonstrated that the frequency of CD8+ T cells expressing exhaustion markers (PD-1, TIM3 and LAG3) were significantly higher both at the tumor site and systemically in obese mice compared to their lean counterparts implicating leptin as the mediator [21].…”