Background

In the medical field, the 'Obesity Paradox,' which suggests that the higher the Body Mass Index (BMI) of cancer patients, the better the therapeutic effect of Immune Checkpoint Inhibitors (ICI), has long been a mystery. This is because it is contrary to the conventional wisdom that chronic inflammation or metabolic disorders associated with obesity suppress anti-cancer immunity. Previous studies have suggested that metabolic changes in obese patients may stimulate the immune system, but they have not been successful in elucidating the specific mechanisms. Since it is not possible to artificially induce obesity in patients, there is an urgent need for a safe way to mimic the benefits of obesity and improve treatment outcomes.

Key Findings

The research team, led by Professor Daniela Quail of McGill University and Professor Bertrand Routy of the CRCHUM, demonstrated that it is not obesity itself, but the 'interaction between diet and gut microbiota' that determines the key pathway for determining the response to anti-cancer immunotherapy. The team designed an experiment in which they fed genetically unmodified mice a high-fat diet and tracked their response to anti-PD-1 immunotherapy. The results showed that in mice fed a specific high-fat diet, tumor growth was inhibited and survival rates improved.

In particular, the high-fat diet created an environment that promoted the growth of beneficial gut bacteria, Lactobacillus johnsonii. This bacterium metabolizes amino acids derived from the diet and produces a large amount of a metabolite called desaminotyrosine (DAT). The DAT produced is transported through the bloodstream and plays a role in directly enhancing the function of CD8+ T cells, which are immune cells. Specifically, it stimulates CD8+ T cells to secrete more anti-cancer cytokines, such as interferon-gamma (IFNγ) and tumor necrosis factor (TNF), thereby maximizing the killing of cancer cells.

This interaction is consistent with the treatment indicators of actual cancer patients. The research team analyzed plasma samples from patients with non-small cell lung cancer (NSCLC) who had received immunotherapy, and found that the concentration of DAT-related metabolites was significantly higher in the group of patients who had a good response to treatment. In mouse experiments, even a short-term switch to a high-fat diet or administration of DAT 48 hours before the start of immunotherapy resulted in dramatic tumor regression in a lung cancer (HKP1 cell line) model that had previously shown resistance to treatment. In particular, when Lactobacillus johnsonii was transplanted into mice with depleted gut microbiota due to antibiotic treatment, and DAT was co-administered, a strong anti-cancer response was induced, with tumors disappearing completely.

Significance and Prospects

This study clearly shows that cancer patients do not need to maintain a high-fat diet for a long period of time. As demonstrated in mouse experiments, sufficient anti-cancer immune activation can be achieved by a short-term dietary change or supplementation with specific metabolites such as DAT just before the start of immunotherapy. In other words, it suggests the possibility of a precision diet therapy that can increase treatment response while avoiding the cardiovascular risks and side effects of a high-fat diet.

However, there are still many challenges to be solved before this finding can be incorporated into a standard clinical protocol. The differences in metabolic pathways and microbial distribution between animals and humans must be overcome, and the optimal route and dosage for various types of cancer must be determined. To this end, the research team plans to conduct clinical trials to verify the therapeutic efficacy of short-term dietary interventions and specific metabolite supplementation.