A growing body of evidence links the microbiome, which can be altered by diet, with response to cancer immunotherapy. A more difficult task is teasing out the mechanism by which diet might be used to improve immunotherapy outcomes.
“When we think of tumor response to immunotherapy, we traditionally think about the tumor and the tumor microenvironment,” said Jennifer McQuade, MD, University of Texas MD Anderson Cancer Center. “The role of the host has not been studied until quite recently. We can’t change host factors such as age and sex, but we can change diet. The microbiome has become a therapeutic target.”
McQuade spoke Friday, April 8, during the Educational Session Diet, Microbiota, and Cancer Immunotherapies, which explored the links between dietary modification of the microbiome and response to immunotherapy. The session can be viewed on the virtual platform by registered meeting participants through July 13, 2022.
In mice, fecal microbiota transplantation (FMT) can promote immunotherapy resistance to immunotherapy response. Observational studies in humans show strong associations between gut microbiome composition and immunotherapy response.
FMT can double response rates in anti-PD1-refractory melanoma in humans from 10-15 percent to about 30 percent, McQuade said. However, FMT also raises multiple questions about donor selection, scalability, procedural risks, and potential transfer of other diseases, she added.
Probiotics, or bacterial supplementation, can alter the microbiome, but may or may not have a significant impact on treatment response.
Early work in modifying diet to alter the microbiome is promising, McQuade noted. Observational studies showing an association between longer progression-free survival following anti-PD-1 therapy for melanoma and greater diversity in gut microbiota have led to controlled feeding studies testing diet as a drug.
A phase I trial in melanoma survivors found that a diet providing at least 50 grams of fiber daily is tolerable with excellent compliance. Microbiota abundance and diversity improved, McQuade reported, but changes were heterogeneous across the patient population.
Altering the diet brought notable changes to the circulating metabolome, with elevated levels of positive lipids and tryptophan/indoles, and reduced levels of bile acids and inflammatory metabolites. A phase II study of diet and immune effects is currently enrolling melanoma patients.
“Diet change is hard,” McQuade said. “You need long-term change in diet to make sustained changes in the microbiome. A reductionist approach—better understanding the interactions between diet, microbiome, and immune response to rationally design prebiotics—has a lot of appeal. It is easier to take a pill than to change your diet.”
Disrupted relationships between microbiota and immune response contribute to many gastrointestinal diseases, causing T and B cell responses that are specific to the intestinal microbiota, explained Timothy W. Hand, PhD, University of Pittsburgh Medical Center’s Children’s Hospital of Pittsburgh. The current paradigm has commensal bacteria driving the induction of regulatory T cells and IgA-producing B cells that are produced locally and trafficked throughout the body, he added.
Intestinal bacteria that attach to the intestinal epithelium induce potent CD4+ T cell responses. Some responses are protective, whereas other responses produce DNA damage and other negative effects on epithelial cells, Hand said. Colorectal cancer (CRC), as an example, has been associated with specific bacterial taxa in the intestinal microbiota.
“So why not modulate the microbiome to augment antitumor immunity?” he suggested.
Work with Helicobacter hepaticus (Hhep), a colon-adherent bacteria commonly found in laboratory and wild mice colonies, supports the concept.
In mice with induced CRC, Hhep can remodel the tumor microenvironment to increase CD4+ T cells and NK cells and activate tertiary lymphoid structures (TLS), which are associated with improved outcomes in CRC. Hhep colonization upregulates cytotoxic lymphocytes to reduce the colon tumor burden and size.
“If we want to shape the immune system, we need to identify the organisms that adhere to surfaces. We should focus on mucus resident and epithelial adherent bacteria,” Hand said. “Once T cells are activated by these colon-resident bacteria, they can be trafficked throughout the body.”
Actinobacteria, Bacteroides, Firmicutes, Protobacteria, Verrucomicrobia, and other phyla in the microbiota play roles in immune checkpoint blockade response, said Kathy McCoy, PhD, University of Calgary Cumming School of Medicine, Calgary, Canada.
“Immune checkpoint blockade doesn’t work in the absence of a microbiome and response can be transferred to nonresponders with FMT, at least in mice,” McCoy explained. “We need to look beyond taxonomy to identify the mechanism by which the microbiome speaks to the immune system.”
The microbiome produces a variety of bacterial products, metabolites, and peptide mimics to communicate with the immune system, she continued. Short chain fatty acids (SCFAs) and tryptophan metabolites are immune modulators that begin to shape immune response in utero and continue through the lifespan.
Some bacterial species promote immune checkpoint blockade response in mice by inducing Th1 differentiation, McCoy noted. One mechanism produces inosine as a metabolite. Inosine, given orally or systemically, promotes immune checkpoint blockade response in melanoma, CRC, bladder, and other cancers in mice.
Work in other labs has shown similar antitumor activity by the SCFAs butyrate and pentanoate, both microbiota metabolites.
“A high-fiber diet can modulate microbial metabolites in the tumor microenvironment and increase antitumor activity,” McCoy said. “It can also protect against colitis and other toxicities associated with immune checkpoint blockade.”