A study led by Chinese scientists at Tsinghua University in Beijing has demonstrated that the gut microbial metabolite butyrate can directly modulate the antitumor CD8 "killer" T-cell response and improve chemotherapy efficacy through ID2-dependent IL-12 signaling.
Reported in the March 23, 2021, online edition of Cell Metabolism, these findings suggest that manipulating gut microbial metabolites such as butyrate and possibly other short-chain fatty acids (SCFAs) could be effective as a part of cancer immunotherapy.
SCFAs including acetate butyrate, and propionate are produced through bacterial fermentation of dietary fiber, and are the most abundant metabolites in the colon.
"This is the first study to show that gut microbial metabolites facilitate cancer therapy by directly modulating CD8 T-cell immunity and that butyrate directly boosts antitumor CD8 T-cell responses via ID2-dependent lIL-12 signaling," said principal investigator Xiaohuan Guo, a professor in the Institute for Immunology at Tsinghua University School of Medicine. Tumor immunotherapies have shown sustained clinical responses, with CD8 T cells playing a central role in antitumor immunity.
Consequently, reduced CD8 T-cell infiltration or dysfunction within the tumor microenvironment (TME) results in poor clinical outcomes with many cancer therapies, which can be offset by promoting TME CD8 infiltration and function.
Gut microbiota play a central role in human health, including in antitumor efficacy in chemotherapy and immunotherapy by shaping host immunity.
For example, cancer patients treated with antibiotics had lower responses to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy compared with controls. However, treating germ-free mice with fecal matter from anti-PD-1-responding patients improved both tumor control and T-cell responses.
Gut microbiota can regulate dendritic and CD4 "helper" T cells to enhance cancer immunosurveillance and promote therapeutic efficacy. However, it remains unclear how gut microbiota regulates antitumor immunity and whether the microbiota could regulate tumor-infiltrating CD8 T-cell responses.
The gut microbiota synthesizes multiple metabolites, some of which appear to affect cancer development and influence systemic immune responses.
Various studies have shown that the fecal SCFA concentration is closely related to colorectal cancer (CRC) incidence and that butyrate directly regulates apoptosis and proliferation of colorectal cancer cells and colon stem cells.
"Compared with healthy people, CRC patients show reduced fecal SCFA concentrations, [suggesting that] the fecal SCFA level could serve as a biomarker for CRC risk, especially for colitis-associated colorectal cancer," Guo told BioWorld Science.
SCFAs such as acetate and butyrate may also influence autoimmune CD8 T-cell responses and can protect against diabetes.
These data suggest that gut microbial metabolites could promote anticancer immunity and improve therapeutic efficacy, suggesting that microbial metabolite manipulation might be effective as a part of cancer therapy.
These possibilities were investigated in both mice and humans in the new Cell Metabolism study.
"We treated mice with butyrate-containing drinking water, by intraperitoneal injection and with a butyrate-containing diet, all of which worked well," Guo said.
Importantly, gut microbial metabolites, especially butyrate, were shown to promote the efficacy of oxaliplatin by modulating CD8 T-cell function in the TME in mice.
The team used several different CRC mouse models in their study, including the cell transplant models Mc38 and EG7 and a spontaneous colitis-associated CRC model.
Specifically, butyrate treatment was shown to directly boost the antitumor cytotoxic CD8+ T-cell responses both in vitro and in vivo in an ID2-independent manner by promoting the IL-12 signaling pathway.
In addition, said Guo, "butyrate also induced ID2 and interferon (IFN)-gamma expression by human CD8 T cells isolated from healthy volunteers in vitro, and the ID2 expression level was positively correlated with the IFN-gamma expression level, indicating that butyrate may also be used as a part of cancer therapy in humans."
In humans, "we have collected serum samples from oxaliplatin-treated cancer patients and examined the butyrate levels in responders and nonresponders," explained Guo. "Serum from cancer patients who responded to oxaliplatin showed significantly higher abundance of butyrate than that of nonresponding patients."
Interestingly, a 2020 study had reported that "fecal SCFA levels in immunotherapy responders were also much higher that in nonresponders," noted Guo.
"Compared with their data, the difference between oxaliplatin responders versus nonresponders [in our study] was not so dramatic, possibly because we examined peripheral blood SCFAs, which are much lower than SCFAs in feces," he suggested.
Together, these findings suggest that butyrate could promote antitumor therapeutic efficacy through the ID2-dependent regulation of CD8 T-cell immunity, suggesting gut microbial metabolites could be effective as a part of cancer therapy.
If this is indeed the case, "then we could consider treating chimeric antigen (CAR-T) or T-cell receptor-engineered (TCR-T) cells with butyrate before transferring them into the patients to increase its efficacy in the future," said Guo.
"In addition, our results indicate that butyrate might be used to assist a variety of antitumor treatments, including oxaliplatin, PD-L1 antibody and adoptive T-cell transfer (ACT) therapy."