In a paper published on 12 November 2018 in Nature Medicine, William Murphy of the University of California Davis School of Medicine, Sacramento, USA and colleagues described a paradoxical impact of obesity on cancer: heightened immune dysfunction and tumour progression, but also greater antitumour efficacy and survival after immune checkpoint blockade which directly targets some of the pathways activated in obesity. 

Impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. In this latest research, the authors demonstrated, across multiple species and tumour models, that obesity results in increased immune aging, tumour progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-(L)1 blockade in both tumour-bearing mice, as well as on clinical outcomes in patients with cancer treated with immune checkpoint blockade stratified by body mass. 

The authors wrote in study background that despite success of PD-(L)1 blockade in multiple malignancies, these therapies fail to generate sustained benefits in most patients. Extensive efforts are underway to elucidate biomarkers and mechanisms of response. Many studies have focused on the tumour microenvironment, as well as mutational or antigenic load, but patient-associated factors such as sex, age, body mass index (BMI) and immunological history are also likely to profoundly impact immune responses and yet are poorly understood. 

Obesity, defined by increased BMI (≥ 30 kg/m2), reflecting visceral fat accumulation, has been associated with numerous comorbidities such as diabetes, heart disease and cancer. Although obesity is characterised by a ‘metainflammatory’ state with dysregulated immune responses and the concept that obesity results in an immune aging effect, termed inflammaging, little is understood about the impact of obesity on immune responses during cancer progression and immunotherapy. This is confounded by the use, in most preclinical cancer models, of young lean mice that fail to recapitulate the clinical scenario of elderly patients with cancer. 

Surprisingly, recent clinical analyses demonstrate that obesity is associated with improved response and survival of patients with cancer treated with targeted therapy and immune checkpoint blockade, although a mechanistic link was not elucidated. 

In this report, the authors demonstrated for the first time, across multiple species and tumour models, that obesity increases T cell aging resulting in higher PD-1 expression and dysfunction, which is driven, at least in part, by leptin signalling. They also observed increased tumour progression in the setting of obesity, and this was probably due to immunosuppression as well as direct (metabolic and hormonal) effects. However, the PD-1-mediated T cell dysfunction in obesity remarkably left tumours markedly more responsive to immune checkpoint blockade. Importantly, these preclinical findings are corroborated by clinical data demonstrating significantly improved outcomes in obese patients with cancer treated with PD-(L)1 inhibitors. 

These findings validate and provide a mechanism for a recent report in obese patients with melanoma showing improved outcomes with immunotherapy. In that study, the effect was limited to male patients with melanoma, whereas the latest clinical data extend across cancer types and demonstrate a positive effect even when controlling for sex. 

Although the latest study focuses on PD-1-mediated T cell dysfunction induced by obesity, sex and other factors such as age, genetics, metabolic dysregulation, gut microbiome, dietary differences and the duration of obesity probably confound the effects of obesity on the immune system and warrant further study. 

The study team focused on leptin as a mechanism of obesity-induced T cell dysfunction, given that STAT3, a major downstream transcription factor of the leptin receptor, has known binding sites in the promoter region of PD-1 and has been implicated in driving expression of PD-1 in human and murine cancers. However, it is important to recognise that these molecules have broad pleiotropic effects, and other pathways are probably implicated. The impact of leptin and obesity on other immune cells is also likely to be important. The results also suggest that targeting the leptin receptor on activated T cells or CAR T cells in immunotherapy may be of use to augment T cell function, particularly in high-leptin circumstances. 

Overall, the data suggest that obesity-associated inflammaging results in increased T cell aging and induction of normal suppressive pathways to counter this chronic inflammatory state. In obesity, PD-1-mediated immune suppression may be a mechanism to protect against possible autoreactive or hyperactive T cell responses induced by chronic inflammation. Importantly, the linkage of obesity and leptin to PD-1 and T cell dysfunction in cancer progression appears remarkably robust in both mouse and human studies. It remains to be determined whether obesity increases PD-1-positive CD8 T cells in a broad range of human cancers and whether this mechanism also contributes to the increased incidence of cancer in obese patients. 

Furthermore, it remains to be delineated clinically whether the environment in the obese state results in greater T cell activation and function once immune checkpoint blockade is applied. It is unclear whether obesity may impact the survival of patients with cancer by other non-immune factors as well. In that regard, obesity should not necessarily be regarded as a positive prognostic factor in cancer but rather as a potential mediator of immune dysfunction and tumour progression that can be successfully reversed by PD-(L)1 checkpoint inhibition resulting in heightened efficacy. 

The findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. The findings highlight the contrasting and paradoxical effects, both positive and negative, of obesity on cancer immune responses in the context of immunotherapy. 

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The datasets generated during and/or analyzed during the current study are available in the NCBI BioSample repository. 

This study was funded by multiple US NIH grants, the California National Primate Research Center base operating grant, the UC Davis Comprehensive Cancer Center Support Grant and the UC Davis Mouse Metabolic Phenotyping Center grant. This research was supported in part by the Intramural Research Program of the NIH, NCI, NHLBI and Center for Cancer Research.

Reference

Wang Z, Aguilar EG, Luna JI et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine; Published online 12 November 2018. doi: 10.1038/s41591-018-0221-5.

This article is a press release of a study published in Nature Medicine. Read the original here.