The advent of immune checkpoint inhibitors (ICI) has improved the overall survival of patients with a variety of malignancies. However, the problem of drug resistance to ICI therapy ( remains a major obstacle limiting its clinical application. The development of drug resistance is associated with multiple factors, including the level of PD-L1 expression in tumor cells, the tumor microenvironment, and the mutational load of genes that determine the cancer-immunecheck point.

Recent macrogenome sequencing studies reveal that the gut microbiota is another key mediator of this tumor immune modulation site. It has been shown that the use of antibiotics prior to initiating ICI therapy decreases gut microbiota diversity in patients with advanced non-small cell lung cancer and will lead to poor treatment outcomes. The use of gut microbiota as a therapeutic adjunct to ICI has emerged as a new direction to address ICI treatment resistance.

On January 14, 2022, a team of Canadian, Swiss, and French researchers published in the prestigious journal Cancer Discovery an article entitled "A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiota", demonstrating for the first time that castalagin, isolated from Camu-camu (CC), alters the gut microbial composition through direct interaction with intestinal commensal bacteria and reshapes the tumor microenvironment, stimulating a stronger anti-PD-1 response and thus effectively overcoming the drug resistance problem.

Camu camu, is native to the upper Amazon rainforest of the Republic of Peru and resembles a grape with a 2-3 cm diameter fruit, which has a beautiful purple-red color when ripe and an almost translucent white flesh. The jam fruit contains a very high dose of natural vitamin C, 60 times more than citrus, and is thought to have antioxidant and anti-inflammatory activity. In addition, scientists have recently discovered that CC fruit also exerts protective prebiotic effects by increasing the abundance of mucinophilic Akkermansia and Bifidobacterium in the intestine to alleviate obesity and associated metabolic disorders in mice.

In this study, we discovered that combining CC with anti-PD-1 therapy reduced tumor growth more effectively than either treatment alone. CC supplementation partially alleviated medication resistance in a mouse model of anti-PD-1 treatment-resistant breast cancer. Further research demonstrated that CC's anticancer activity was dependent on intestinal flora and that it might increase microbiome diversity, resulting in a change in microbiome composition. The researchers also found that the antitumor activity of CC was also dependent on CD8+ T cells and was associated with the abundance of the immunogenic bacteria Ruminococcus, Christensenellaceae R-7 group, Bilophila, and A. muciniphila.

With the help of high performance liquid chromatography (HPLC), the study identified a bioactive polyphenol of CC, chestnut ellagitannin, as its molecular basis for the antitumor effect. To back up their findings, the researchers replicated the previous procedures using chestnut ellagitannins and found that chestnut ellagitannins could change the gut microbial composition, generate a systemic immunological response, and influence CD8+ T cells on their own. Further research demonstrated that chestnut ellagitannins could overcome anti-PD-1 resistance to some extent, and that their anticancer effects were linked to ruminal cocci abundance. Chestnut ellagitannins were found to preferentially bind to the cell membrane of Ruminococcus, triggering the anticancer action.

This study revealed for the first time that chestnut ellagitannins isolated from CC have antitumor effects through direct interaction with symbiotic bacteria, thereby reshaping the tumor microenvironment. Furthermore, in a preclinical anti-PD-1 resistance model, chestnut ellagitannins were able to re-establish the effectiveness of anti-PD-1 therapy. This is the first study to demonstrate microbially-dependent antitumor effects of a single polyphenol as a prebiotic, paving the way for future clinical trials using chestnut ellagitannin as an ICI adjuvant in oncology patients.

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