The microbiome and cancer immunotherapy

Introduction

I recall during my directorship of the National Cancer Institute (2006–2010) being appointed as one of several National Institutes of Health (NIH) institute directors to serve on an NIH external advisory committee charged with advising the NIH director regarding areas of science ready for prioritization. Consensus was quickly reached that the microbiome and its relationship to health and disease was primed for a significant research investment. ^, Discussion by those participating recognized that the organisms residing in the body such as bacteria, viruses, fungi, yeast, protozoa, and archaea, along with their genomes and metabolic products, actually can be considered an organ system in their own right. Though these varied organisms comprising the microbiota may be found virtually anywhere on the body, focus has been on sites such as skin and mucous membranes of the body’s external facing structures and the epithelial linings of the lungs, genitourinary tract, and gastrointestinal system.

As a result, in 2007 the NIH launched the Human Microbiome Project (HMP). The first phase of HMP (2007–2012) was focused on identifying and characterizing the human microbiota. ^, The second phase was launched in 2014 as the Integrative HMP (iHMP; http://ihmpdcc.org ) with the goal of generating integrated longitudinal data sets of microbiota biologic properties in association with disease conditions. An emphasis was placed on establishing the technologies of 16S rRNA gene profiling, whole metagenomic shotgun sequencing, whole genome sequencing, metatranscriptomics, metabolomics, and immunoproteomics as tools to study the human microbiota and how this complex system integrates as a functioning organ with the host. Current science in this field is greatly enabled by advances in computational biology, artificial intelligence, machine learning, and powerful computer systems capable of integrating large data sets.

The technologies originally developed to accomplish the Human Genome Project, as one can readily understand, were enabling to the iHMP. The iHMP was designed to be an interdisciplinary effort of disease-based or related projects. The goal of the iHMP has been to define the genetic and functional diversity of the organ specific microbiomes and their relationship to disease(s). The NMP and iNMP research projects demonstrated that each individual has their unique composition of microbiota strains. Though current studies in cancer have focused on bacteria, other microorganisms including the commensal viruses, fungi, and archaea cannot be neglected because they most certainly also have a role in cancer and immuno-oncology (for an in-depth review, see The Integrative HMP Research Netword Consortium, Voth and Khanna, and the NIH Human Microbiome Portfolio Analysis Team ).

Studies of the gut microbiome, for example, demonstrated the importance of maternal colonization and a period during newborn development with flora of low diversity, referred to as the period of “founder species.” The gut microbiome is seeded in utero and evolves early in life to a mature colonization. Composition of the gut microbiota is influenced by geography, ethnicity, diet, mode of delivery (vaginal vs cesarean section), illness, and use of antibiotics during the host’s early development. The intestinal microbiome is estimated to contain over 100 trillion microorganism cells that encode more than 3 million genes. The gut microbiota with its complex organization of microbes exists in symbiosis with the host and provides a remarkable array of protein products that play a critical role in host physiology.

During the past decade as a result of the NIH investments in the NMP, research has found increasing evidence for a strong relationship between the gut microbiome and cancer, including colon and rectum, esophageal, gastric, pancreatic, lung, melanoma, breast cancer, as well as hematologic malignancies. In this chapter, we will review what is known regarding the role the gut microbiome plays in the initiation and progression of cancer as well as its effect on cancer treatment especially immunotherapy.

The microbiome and immune system development

The bacterial component of the human microbiota is by far the most researched of the microbiota communities. These microbiota communities consist of bacteria, archaea, bacteriophages, viruses, fungi, and protozoa. The colonies of the microbiota can be found on the surfaces of digestive tract, respiratory system, urogenital tracts, and skin. ^, It is demonstrated that the host immune system, both innate and adaptive, evolved along with the colonization of the host microbiota to establish a healthy coexistence between the organisms of the microbiota and the responding capability of the host immune system. ^, This evolving relationship actually begins in utero and reaches a mature status somewhere between the ages of 3 and 5 years. This commensal relationship and the integrity of the immune system, however, are ongoing throughout life. The integrity and cellular makeup of the immune system is subject to alteration or impairment throughout life as a result of changes in the microbiota. Gut microbiota forces impacting the integrity of the immune system may be as simple as host dietary changes and as complex as may occur with the onset of certain chronic diseases and the administration of antibiotics ^, (for an in-depth review, see Maynard et al. ).

In the gastrointestinal (GI) tract, the Bacteroidetes and Firmicutes phyla account for an estimated 90% of the bacterial colonies. The remaining 10% is made up of colonies of the phyla Actinobacteria, Cyanobacteria, Fusobacteria, Proteobacteria, and Verrucomicrobia. The greatest bacterial density in the GI tract occurs in the colon. Research using advanced genomic techniques has demonstrated that the GI microbiome actively affects a number of host functions including metabolism, immunity, the development and progression of cancer, and the host responses to pharmacogenomic interventions. ^,

The actual development of the immune system begins in utero, as does the growing relationship of the immune system with the developing fetal microbiota. Because the initial microbiota of the neonate is acquired by vertical transmission from the mother, there exists an inherited tolerogenic immunity to the colonizing microbiota. It has been demonstrated that transvaginal delivery is also an important source of seeding the newborn microbiome with the mother’s native and tolerated vaginal microbiota. Breast milk is also an important source of immune regulating factors involved in the early education and formation of the newborn immune system. Breast milk contains a number of immune stimulating factors such as actual live bacteria, protein metabolites, immunoglobulin (Ig) A antibodies, certain immune cytokines, and even cells of the immune system. Accumulating evidence has confirmed the critical role the early seeding and maturation of the newborn microbiota has to the postnatal imprinting and maturation of the immune system. In a sense, the constant priming of the host immune system by an intact microbiome is critical for an immune system ready to optimize the host’s ability to effect efficient antitumor therapies. Any effect on the normal development of the newborn microbiota can affect host immunity throughout life. ^{, , ,}

Conditions that occur in the host required for the host to eliminate an invading pathogen can become a risk to the host if these immune responses become chronic in nature. Such chronic inflammatory responses have the potential to cause dysbiosis within the microbiota and as a result alter host immunity. Host efforts to curb inflammation can be detrimental to the host’s antitumor response. The host’s efforts to curb inflammation can be thought of as being competitive to the host’s capacity to adequately mount a robust antitumor response during the early stages of tumor initiation (for an in-depth review, see Belkaid and Harrison ).