What is already known
Both sex and the gut microbiome can influence the response to immune checkpoint inhibitors (ICIs), a type of cancer immunotherapy that has revolutionized cancer treatment in recent years. In particular, some gut microbiome signatures are associated with higher response to ICIs. Sex-based immune response to ICIs have been also reported and the sex hormone-gut microbiome axis might play a critical role in regulating the response to ICIs.
What this research adds
The involvement of the sex hormone-gut microbiome axis in regulating the antitumor efficacy of ICIs has been demonstrated by several studies. Moreover, there are evidences that manipulating the gut microbiome could regulate the levels of sex hormones and potentially enhance the effectiveness of ICIs in fighting tumors.
Conclusions
The sex hormone-gut microbiome axis plays a critical role in tumor immunotherapy, and further research in this area could lead to the development of novel approaches to cancer treatment.
A recent review published in Gut microbes journal, describes the influence of both sex and gut microbiome on the antitumor efficacy of ICIs, and the interaction between sex hormones and gut microbiome.
It is suggested that manipulation of the gut microbiome could regulate the levels of sex hormones and enhance the antitumor efficacy of ICIs, thereby providing new avenues for tumor immunotherapy.
The response to ICIs may be influenced by the gut microbiome
The gut microbiome can influence the efficacy of ICIs through multiple mechanisms. Studies in mice have found that certain bacterial immunostimulants can enhance the anti-tumor effects of ICIs by strengthening innate immunity and T cell functions. Bacteria may also stimulate the anti-tumor immune response by penetrating mucus and submucosal lymphoid organs or tumor sites. Interestingly, bacteria can ‘imitate’ the tumor-associated antigens leading to the induction of T cell responses. Based on the similarity between gut microbiota and tumor-derived antigens, a therapeutic vaccine has been developed for the treatment of colorectal cancer.
Apart from immunomodulatory microbial components, the effects of gut microbiome on the antitumor immune response to ICIs may be mediated by their metabolites. Indeed, short-chain fatty acids and certain bacterial species that produce them, have been associated with a favorable response to ICIs in cancer patients. Studies in mice have shown that the metabolite butyrate can enhance the antitumor cytotoxic CD8+ T cell response and increase the efficacy of cancer therapy; whereas inosine produced by certain bacteria could improve the response to ICIs by activating anti-tumor T cells. However, some microbial metabolites, such as kynurenine, may decrease the antitumor efficacy of ICIs. Interestingly, it has been found that ICIs themselves can also alter the composition of the gut microbiome, but the underlying mechanisms of the impact of ICIs on gut microbiome have yet to be clarified.
Sex-based differences in gut microbiome
Sex-based differences in microbiota composition have been observed in both animal models and human, with women generally having higher alpha diversity. The Firmicutes to Bacteroidetes (F/B) ratio, a marker for gut dysbiosis, tends to be higher in women, and a lower abundance of Bacteroidetes in women may contribute to their higher microbial alpha diversity. The gut microbiome in cancer patients also shows sex-based differences and distinct changes in microbial alpha diversity as well as community composition was observed in colorectal cancer development.
Some sex hormone-associated bacteria have been identified. For instance, total levels of urinary estrogen in men and postmenopausal women were significantly associated with fecal Clostridia. The abundance of certain bacteria such as Acinetobacter, Dorea, Ruminococcus, and Megamonas was positively correlated with serum testosterone levels in men, while the abundance of Slackia and Butyricimonas is negatively correlated with serum estradiol levels in women. It has been shown that progesterone supplementation increases the abundance of Bifidobacterium in mice and in vitro, indicating that favorable metabolism of sex hormones by certain bacterial taxa may alter gut microbial composition.
Sex hormone levels could be regulated by the gut microbiome.
The bidirectional interaction between sex hormones and gut microbiome is defined as the ‘microgenderome’. Sex-specific microbiome profiles that emerge after puberty contribute to the levels of sex hormones, and certain gut microorganisms have the ability to regulate the levels of sex hormones through different mechanisms.
Gut microbes can regulate the levels of sex hormones by participating in the metabolism of sex hormones in the intestine through the expression of certain enzymes. Importantly, human fecal bacteria can carry out a variety of reactions of androgens and estrogens. For instance, Streptococcus mutans, has been identified with the potential of metabolizing progesterone and testosterone. Moreover, gut microbes may also influence gonadal function, such as hormone secretion via the gut-brain axis. Although there is a wide variety of mechanisms by which gut microbiome regulates sex hormone levels, the exact mechanisms have not been fully explored.
Enhancing antitumor efficacy of ICIs: modulating sex hormones levels via gut microbiome manipulation
Trials are ongoing to investigate the potential of combining sex hormone interventions with tumor immunotherapy, mainly in prostate and breast cancer. However, many trials have focused on sex-hormone-dependent cancers so it would be crucial to determine whether combination therapy is superior to ICI monotherapy for non-sex hormone-dependent cancers too. Recent studies show that the gut microbiome can contribute to endocrine resistance in some prostate cancer patients and that manipulating the microbiome with specific antibiotics can downregulate testosterone levels and enhance antitumor efficacy of therapies. These findings confirme the feasibility of improving the efficacy of antitumor immunotherapy by modulating levels of sex hormones via manipulation of the gut microbiome with narrow-spectrum antibiotics.
Other methods, such as FMT, probiotics, and prebiotics, have also been tested to modulate the gut microbiome and improve ICI therapy, but it is unclear whether sex hormones play a role in this process. Further studies are needed to clarify the potential synergistic effect of sex hormones and microbial metabolites on ICI therapy.
In conclusion, numerous evidences demonstrate the involvement of the sex hormone-gut microbiome axis in regulating the antitumor efficacy of ICIs. Modulation of the sex hormone receptor signaling pathway can improve the response to ICI therapy and manipulation of the gut microbiome via antibiotics or other methods can regulate the levels of sex hormones and improve the efficacy of antitumor immunotherapy. However, further research is needed to fully elucidate the underlying mechanisms and confirm the importance of the sex hormone-gut microbiome axis in tumor immunotherapy.
