86P - Regulation of cancer progression through the gut microbiome and immuno-nutrition

Background

Obesity rivals smoking as a leading modifiable risk factor for cancer mortality, accounting for up to 20% of adult cancer-related deaths. Diet is a crucial factor in obesity development and significantly influences cancer growth. Paradoxically, high BMI has been linked to improved immune checkpoint inhibitor (ICI) efficacy in various cancers, challenging the notion that obesity is universally detrimental in cancer contexts. To address this paradox, we devised a panel of 12 diets that mimic human dietary patterns in mouse models, observing vastly different rates of cancer growth and ICI response. Surprisingly, not all obesity-inducing diets were beneficial for ICI, prompting an investigation into the cause of these disparities. The microbiome's pivotal role in regulating cancer and therapy through its profound influence on the immune system is well-supported, with gut dysbiosis and antibiotic use increasing cancer risk and blunting ICI response in patients and fecal microbial transplant from ICI-responsive patients shown to enhance ICI therapy. We propose that the interplay between diet and systemic inflammatory responses to gut microbiota contributes to the variations in ICI response across obesity-inducing diet models.

Methods

To track the gut microbial composition changes in mice during the development of our 12-diet model, we collected stool samples and performed 16s rRNA sequencing. The analyses focused on four obesity-inducing diets: American, High Fat, Ketogenic and Mediterranean.

Results

Analysis unveiled differences in gut bacterial composition at the phylum level across all four obesity inducing diets. However, family-level changes were associated with ICI response in a diet-specific manner. To delve deeper into these findings, we conducted metagenomic sequencing, revealing specific species associated with ICI response in preliminary analyses.

Conclusions

These findings suggest that diet-induced gut microbial modifications, in the context of obesity, may influence ICI efficacy, and offers promising avenues for the development of new therapeutic approaches that utilize the microbiome to enhance cancer treatment outcomes.

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.