The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy

Abstract

The microbiome is receiving significant attention given its influence on a host of human diseases including cancer. Its role in response to cancer treatment is becoming increasingly apparent, with evidence suggesting that modulating the gut microbiome may affect responses to numerous forms of cancer therapy. A working knowledge of the microbiome is vital as we move forward in this age of precision medicine, and an understanding of the microbiome's influence on immune responses and cancer is key. It is also important to understand factors influencing the gut microbiome and strategies to manipulate the microbiome to augment therapeutic responses.

Keywords: cancer; cancer immunosurveillance; gut microbiome; immunity; immunotherapy; immunotherapy response; immunotherapy toxicity; microbiome; microbiome manipulation; microbiota.

Conflict of interest statement

Declaration of interests:

J.A.W. and V.G. are inventors on a U.S. patent application (PCT/US17/53717) submitted by The University of Texas MD Anderson Cancer Center that covers methods to enhance checkpoint blockade therapy by the microbiome. J.A.W is a clinical and scientific advisor at Microbiome DX. V.G. is a consultant at Microbiome DX. CS, AR and BH report no relevant conflicts of interest or financial disclosures.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1.. The Microbiome and Immunity.

Commensal organisms within the lumen of the gut have profound influences on the immune system at the local level within the gut mucosa, in draining mesenteric lymph nodes, and systemically. The immune system likewise can alter the gut microbiota. Goblet cells create a thick mucous protective layer covering the mucosa; this mucousal layer is largely deficient in germ-free animals. Plasma cells in the lamina propria secrete IgA into the lumen of the gut. Paneth cells secrete a number of anti-microbial peptides; their activity is amplified in response to signaling from local immune cells in response to the microbiota. Bacterial metabolites or bacteria themselves can activate local DCs which migrate to the draining lymph nodes to activate naïve T cells to effector T cells, Tregs or Th17 cells which can migrate back to the gut mucosa or enter systemic circulation. Specific metabolites or bacterial byproducts can alter the dendritic cell in a fashion that allows them to skew towards a Treg versus Th17 phenotype. Tregs function in secreting IL10, creating a local anti-inflammatory cytokine milieu. Th17 cells, meanwhile, produce IL17 which can increase Paneth cell production of antimicrobial peptides and can function in recruiting PMNs from the bloodstream. Some bacterial metabolites can enter the bloodstream directly further altering the systemic immune system.

Figure 2.. Phylogenetic tree summarizing previously established links between the gut microbiome, treatment outcomes and toxicities in cancer patient populations.

A phylogenetic tree was constructed using evolutionary distances with the phyloT software (Letunic and Bork, 2016), to depict phylogenetic similarity (or lack thereof), of all bacterial taxa reported to be associated with response or toxicity to immune checkpoint blockade in human studies, moving from broader (kingdom) to more specific (species) taxonomies from inside-out. Bacterial taxa are labeled according to publication (colored dots) of origin and shaded (R=treatment response, light blue; NR=treatment non-response, light red; T=toxicity, light green; NT=non-toxicity, light purple) according to the phenotype(s) of association in the various studies included