Influence of the Microbiome in Cancer

One session at the 2022 Cholangiocarcinoma Foundation annual meeting focused on the role of microbiome in the pathogenesis of hepatobiliary cancers.

The human gut microbiome is a unique microbial profile including bacteria, viruses, and fungi. It is estimated that there are >100 times more microbial genes than the human genome itself.¹ The microbiome is influenced by diet, medications, geography, lifestyle, genetics, and many other factors.²

Dr Gregory Sepich-Poore from the University of California San Diego, cofounder of the microbiome-driven cancer detection company Micronoma, noted that “tumors are not sterile entities. Microbial DNA is detectable consistently in blood/plasma. Bacteria, viruses, and fungi all likely coexist in intratumor microbiomes.” Moreover, microbiomes that are specific to cancer type and tissue type have been described.

Dr Tim F. Greten from the National Institutes of Health Center for Cancer Research hypothesized that “under normal conditions, in the event of liver changes such as fibrosis, a change in the microbiota composition occurs. This may be induced by a change in bile acid metabolism that causes dysbiosis and a leaky gut, which means that bacteria can transmigrate easier into the gut epithelium. They go through the portal vein into the liver and via a TLR4-mediated mechanism leading to [myeloid-derived suppressor cell] accumulation that suppresses immune responses and promotes tumor growth.”

Dr Katie Kelley from the School of Medicine at the University of California San Francisco discussed the role of the microbiome in predicting immunotherapy response. Mao and colleagues reported that specific gut microbiome composition correlated with immune checkpoint inhibitor efficacy outcomes across a variety of tumor type cohorts. In their study of 65 patients with hepatobiliary cancers, gut microbiome composition was associated with the clinical response to anti–PD-1 immunotherapy.³ Specific gut microbiota signatures may also be associated with toxicity to immune checkpoint inhibitor (ICI) therapy.⁴

However, there is no current role for microbiome biomarker testing due to current limitations in microbiome data, including assessment of small and retrospective cohorts with significant heterogeneity and inconsistency as well as lack of standardized methodologies. Other confounding factors include selection bias as well as population and treatment heterogeneity. “Prospective studies are warranted to validate microbiome-based biomarkers for ICI response and toxicity,” Dr Kelley said.

Dietary-induced changes in the gut microbiome have been shown to affect response to immunotherapy.⁵ In particular, consumption of a higher-fiber diet showed improved progression-free survival in 128 patients with melanoma who received ICI therapy. However, supplemental probiotics did not augment the efficacy of ICIs in this setting. The most pronounced survival benefit was observed in patients with sufficient dietary fiber intake and no probiotic use. Based on these data, a high-fiber diet may be recommended in patients with CCA who are treated with an ICI.

The impact of antibiotics on ICI efficacy in patients with hepatobiliary carcinoma (HCC) has not been established. In a large population of patients with HCC, early antibiotic exposure was not detrimental to efficacy outcomes with ICI therapy.⁶

Dr Sepich-Poore concluded the presentation by advising oncologists to “consider how their therapies interact with the gut and tumor microbiomes.”

References

1. Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021;371:eabc4552.
2. Rinninella E, Raoul P, Cintoni M, et al. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms. 2019;7:14.
3. Mao J, Wang D, Long J, et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J Immunother Cancer. 2021;9:e003334.
4. Andrews MC, Duong CPM, Gopalakrishnan V, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med. 2021;27:1432-1441.
5. Spencer CN, McQuade JL, Gopalakrishnan V, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021;374:1632-1640.
6. Fessas P, Naeem M, Pinter M, et al. Early antibiotic exposure is not detrimental to therapeutic effect from immunotherapy in hepatocellular carcinoma. Liver Cancer. 2021;10:583-592.