The Impact of Intratumoral and Gastrointestinal Microbiota on Systemic Cancer Therapy

Comprehensive and cost-effective characterization of gut and tumor microbiota can help understand dynamic association between commensal signatures and a phenotype. Efficacy of the therapeutic treatment is strongly influenced by the diversity and abundance of the resident commensal microbiota. The microbiota has a potential to both induce deleterious and beneficial effects on host immune responses. A perpetual and dynamic crosstalk between the microbial community and host immune responses can dictate therapeutic outcomes. Microbial metabolites represent functional capabilities of microbiota and play a key role in exerting distinct immunomodulatory effects. The microbiome has the potential to be utilized as both a diagnostic tool, as well as a therapeutic adjunct in the context of anticancer therapy. The human microbiome is a complex aggregate of microorganisms, and their genomes exert a number of influences crucial to the metabolic, immunologic, hormonal, and homeostatic function of the host. Recent work, both in preclinical mouse models and human studies, has shed light on the impact of gut and tumor microbiota on responses to systemic anticancer therapeutics. In light of this, strategies to target the microbiome to improve therapeutic responses are underway, including efforts to target gut and intratumoral microbes. Here, we discuss mechanisms by which microbiota may impact systemic and antitumor immunity, in addition to outstanding questions in the field. A deeper understanding of these is critical as we devise putative strategies to target the microbiome. The human microbiome is a complex aggregate of microorganisms, and their genomes exert a number of influences crucial to the metabolic, immunologic, hormonal, and homeostatic function of the host. Recent work, both in preclinical mouse models and human studies, has shed light on the impact of gut and tumor microbiota on responses to systemic anticancer therapeutics. In light of this, strategies to target the microbiome to improve therapeutic responses are underway, including efforts to target gut and intratumoral microbes. Here, we discuss mechanisms by which microbiota may impact systemic and antitumor immunity, in addition to outstanding questions in the field. A deeper understanding of these is critical as we devise putative strategies to target the microbiome. type of anti-infectious or antitumor therapy which involves the transfer of cells in a patient. These cells can be derived from the patient itself (autologous transfer) or from different individuals (allogeneic transfer). a cancer treatment uses cells originated from a patient or individual and generates tumor-specific immune cells infused into cancer patients with the goal of recognizing, targeting, and killing tumor cells. mean species diversity within a single microbiota sample. monoclonal antibody, mainly used as cancer immunotherapy. It blocks the programmed death-1 (PD-1) immune checkpoint expressed on the surface of immune CD8+ T cells, thus rejuvenating them from exhaustion to sustain an antitumor response. a read refers to the sequence of a cluster that is obtained after the sequencing process is complete. Users receive sequencing data as unassembled reads. Sequence assemble refers to the aligning and merging of fragments from long DNA sequencing in order to reconstruct the original genome. a live attenuated strain of Mycobacterium bovis; FDA approved for primary therapy of in situ bladder carcinoma. mean species diversity across different microbiota samples. generally, antibodies that inhibit key checkpoint receptors such as PD-1. When these proteins are blocked, the ‘brakes’ on the immune system are released and cytotoxic T cells can kill certain cancer cells more effectively. an important component of genomic diversity; it is a type of structural variation, defined as a type of duplication or deletion event, of one kilobase (kb) or larger, in which sections of the genome are present in comparison with a reference genome. a precise method of PCR; can be used for direct quantification and clonally amplified nucleic acid strands such as DNA, cDNA, or RNA; target applications include mutation detection and copy number variations. also referred to as dysbacteriosis of the gut, in contrast to the eubiotic gut, wherein a microbial imbalance or maladaptation takes place. Dysbiosis can be caused by changes in diet, antibiotics, and/or chronic inflammation. characterized by a dominance of potentially beneficial microbial species, mainly belonging to two bacterial phyla, Firmicutes and Bacteroides. A healthy, or eubiotic gut, is a balanced but flexible ecosystem that tolerates pathogens from flora. significantly higher alpha-diversity and relative abundance of Ruminococcaceae bacteria relative to an ‘unfavorable’ microbiome. cytotoxic agent used in the treatment of multiple solid and hematological tumors. key component of the mucosa associated lymphoid tissue; works in tandem with the immune system to protect against infection in the gut. a series of protocols and techniques for the efficient screening of a large number of extinction culture attempts for growth and subsequent identification. United States National Institutes of Health research initiative to improve the understanding of the microbial flora involved in human health and disease. molecules which regulate the activity of the immune system and self-tolerance. These checkpoints can be stimulatory (e.g., CD28, CD40) or inhibitory (e.g., CTLA-4, PD-1). catalyzes the first and rate-limiting step in the oxidation of L-tryptophan to N-formylkynurenine. cytosolic protein complexes which activate inflammatory responses through the maturation and secretion of cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). cytotoxic agent mostly used to treat colon cancer and small cell lung cancer. matrix-assisted laser desorption ionization time-of-flight mass spectrometry is a rapid, accurate, and cost-effective method of microbial characterization and identification. refers to sequence similarities between foreign and self-peptides, which can lead to the crossactivation of autoreactive T or B cells by peptides derived from pathogens. a catch-all term to describe multiple modern high-throughput sequencing techniques (Illumnia Solexa, Roche 454, Proton/PGM, and SOLiD sequencing) and applies to genome sequencing, genome resequencing, transcriptome profiling (RNA-Seq), DNA–protein interactions (ChIP-sequencing), and epigenome characterization. All of these methods allow for sequencing of DNA and RNA quickly and accurately. used to classify groups of closely related species, a pragmatic proxy for microbial species at different taxonomic levels, often grouped by DNA sequence similarity of a specific taxonomic marker gene. cytotoxic agent mostly used to treat colon cancer. mainly expressed by innate immune cells; germline-encoded host receptors, which are specialized in the detection of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). a type of artifact common in whole-genome amplification; results when the end product of the amplification method does not dependably recapitulate the starting DNA. gene coding for a component of the 30S small subunit of a prokaryotic ribosome; used to reconstruct phylogenies. T cells with a TCR composed of two glycoprotein chains, alpha and beta TCR chains (95% of T cells). T cells with a T cell receptor on their surface made of one gamma chain and one delta chain. In high abundance in the gut and other mucosae. a subpopulation of T cells that modulate the immune system, maintaining self-tolerance and homeostasis. Generally, Tregs are immunosuppressive and downregulate induction and growth of effector CD8+ T cells. induced in parallel to Th17 cells and, like Th17, these polarized cells are proinflammatory; they produce INFγ and TNF-β. transforming growth factor β, interleukin 6 (IL6), IL21, and IL23 can differentiate naïve CD4+ T lymphocytes into the Th17 subtype. Can contribute to local and chronic inflammation through proinflammatory cytokines (e.g., IL-17, IL-21, IL-22), which mainly recruit neutrophils. T cell immunoreceptor with Ig and ITIM domains; immune receptor found on T cells and natural killer (NK) cells. Toll-like receptors are single, membrane-spanning, noncatalytic receptors which are expressed on innate immune cells such as macrophages and dendritic cells. They recognize structurally conserved molecules derived from microbial pathogens. or shotgun metagenomics, allows for the comprehensive sampling of all genes in all organisms present in a given complex sample. Excellent tool to evaluate bacterial diversity and detect the abundance of microbes in various environments.