74P - Obesity regulates tumor progression and sensitivity to checkpoint blockade through the diet-microbiota-immunity axis

Background

Globally, more people are overweight/obese than underweight, and obesity is associated with increased risk and mortality of at least 13 types of cancer. Paradoxically, obesity is not detrimental in all cancer contexts. For example, obesity is associated with improved immune checkpoint inhibitor (ICI) efficacy in a variety of cancer types. While there is a body of literature demonstrating that the gut microbiome impacts ICI efficacy in preclinical models and human clinical trials, it is unknown how these observations relate to dietary habits and/or body weight.

Methods

To investigate how diet influences cancer progression, we exposed our preclinical mouse model of lung cancer to 12 unique diets that lead to varying amounts of weight gain and metabolic dysfunction over 15 weeks. To identify biological mechanisms driving ICI sensitivity, we characterized peripheral blood and tumor-infiltrating immune cells by spectral flow cytometry. To identify diet-induced intestinal bacteria signatures, we performed 16s rRNA sequencing to profile the gut microbiota.

Results

We found that tumor growth and anti-PD-1 sensitivity are diet-dependent and vary significantly between obesity-promoting diets. Flow cytometric analysis of the peripheral blood revealed an inverse correlation between T cells and weight gain, and positive correlation with monocyte populations. However, these immune changes at-steady state were not associated with tumor growth or ICI sensitivity. Interestingly, the gut microbiome stabilized after only 3 weeks following diet enrollment, independent of significant weight gain over the diet enrollment period. Further, 3 weeks on diet was sufficient to phenocopy tumor growth kinetics observed after 15 weeks of diet, independent of any major bodyweight changes.

Conclusions

These findings suggest that diet-induced changes to the gut microbiome may be driving differences in tumor growth and ICI sensitivity, and that diet and nutrition can be optimized to maximize the patient population that can benefit from ICI therapy.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Canadian Cancer Society.

Disclosure

All authors have declared no conflicts of interest.