Exploring the Emerging Role of the Microbiome in Cancer Immunotherapy Jessica Fessler1†, Vyara Matson1† and Thomas F
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Fessler et al. Journal for ImmunoTherapy of Cancer (2019) 7:108 https://doi.org/10.1186/s40425-019-0574-4 REVIEW Open Access Exploring the emerging role of the microbiome in cancer immunotherapy Jessica Fessler1†, Vyara Matson1† and Thomas F. Gajewski1,2* Abstract The activity of the commensal microbiota significantly impacts human health and has been linked to the development of many diseases, including cancer. Gnotobiotic animal models have shown that the microbiota has many effects on host physiology, including on the development and regulation of immune responses. More recently, evidence has indicated that the microbiota can more specifically influence the outcome of cancer immunotherapy. Therapeutic interventions to optimize microbiota composition to improve immunotherapy outcomes have shown promise in mouse studies. Ongoing endeavors are translating these pre-clinical findings to early stage clinical testing. In this review we summarize 1) basic methodologies and considerations for studies of host-microbiota interactions; 2) experimental evidence towards a causal link between gut microbiota composition and immunotherapeutic efficacy; 3) possible mechanisms governing the microbiota-mediated impact on immunotherapy efficacy. Moving forward, there is need for a deeper understanding of the underlying biological mechanisms that link specific bacterial strains to host immunity. Integrating microbiome effects with other tumor and host factors regulating immunotherapy responsiveness versus resistance could facilitate optimization of therapeutic outcomes. Keywords: Immunotherapy, Gut microbiome, Anti-PD-1, Immune checkpoint blockade, 16S rRNA gene sequencing, Metagenomics, Germ-free mice, Microbiome-based therapy Background hormones, essential vitamins, and other bioactive com- The human body is a complex ecosystem inhabited and pounds, which cannot be otherwise acquired by the host influenced by an abundance of microorganisms including [2]. These metabolites can modulate various biological bacteria, yeast, fungi, protozoa, archaea, and viruses, all of functions, most notably the immune and nervous systems which collectively constitute the commensal microbiota. [3]. Alterations in the normal microbiota have been re- The commensal microbiota and the human host have ported to contribute to the development of many diseases co-evolved in a mutualistic relationship, in which each [4–15]. In the cancer context, some specific bacteria have benefits the fitness of the other and the two can be collect- been demonstrated to be involved in the process of car- ively viewed as a superorganism. Much recent research cinogenesis [15]. In addition, the microbiota has also been has focused on the bacterial component of the microbiota. implicated in modulating the efficacy and toxicity of can- On average, a healthy human body is comprised of ap- cer therapy, including chemotherapy and immunotherapy proximately 30 trillion cells and is inhabited by approxi- [16]. Preclinical data suggest that modulation of the mately 39 trillion bacterial cells [1]. The collection of microbiota could become a novel strategy for improving genes within the commensal microbiota is defined as the the efficacy of immune-based therapies for cancer, in par- commensal microbiome and vastly outnumbers human ticular checkpoint blockade approaches targeting the genes. The microbiota is capable of synthesizing or trans- CTLA-4 and PD-1 pathways [17, 18]. forming a wide variety of metabolites, including * Correspondence: [email protected] Establishment of commensal bacterial colonization in the † Jessica Fessler and Vyara Matson contributed equally to this work. human host 1Department of Pathology, The University of Chicago, Chicago, IL, USA 2Department of Medicine, Section of Hematology/Oncology, The University In adults the microbiota consists of about a dozen of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL 60637, USA phyla, primarily Firmicutes and Bacteroidetes, © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fessler et al. Journal for ImmunoTherapy of Cancer (2019) 7:108 Page 2 of 15 followed by Actinobacteria, Proteobacteria, Fusobacteria, encoding the 16S rRNA, part of the small ribosomal and others [19]. The relative proportions of these phyla vary subunit in prokaryotes. This is a ubiquitous 1.5kb between individuals and between anatomical sites. The GI gene, containing conserved sequences and hypervari- tract is considered the most impactful site of host-microbe able regions (nine regions: V1-V9), the latter being interactions. Various factors can influence the composition useful for bacterial taxonomic classification, as origin- of the gut microbiota in a given individual, such as the ally described by Woese and colleagues [29]. In the composition of the maternal microbiota, mode of infant de- first step of this technique, a pair of universal primers livery (vaginal vs. C-section), diet, exposure to antibiotics targeting conserved sequences flanking a hypervari- and other medications, germline genetics of the host, and able region are used to generate an amplicon library, environmental factors [20]. Initial microbial exposure may which is then sequenced. To account for sequencing er- occur as early as in utero, where the GI tract of the fetus rors, amplicons which share sequence similarity above a may first be colonized by maternal bacteria through in- certain threshold are grouped into operational taxonomic gestion of amniotic fluid [21, 22]. After vaginal deliv- units (OTUs). A representative amplicon is selected from ery, the neonatal microbiota resembles the mother’s each OTU bin and assigned a taxonomic identity based vaginal microbiota and is undifferentiated across ana- on cross-referencing to pre-existing databases [30–32]. All tomical sites [23], but subsequently becomes shaped other amplicons in the OTU are also assigned the same by the selective pressure of site-specific factors and by identity. Thus, OTU binning can artificially decrease the 3 years of age, an adult-like intestinal microbiota dom- observed diversity of a microbial community [33]and inated by Firmicutes or Bacteroidetes is established. alternative methods for analysis have been proposed [34– After this age, the microbiome composition in a healthy 36]. Because bacterial identification is based on a portion individual reaches a relatively stable state with minor fluc- of the 16S rRNA gene, species level resolution is usually tuations in physiological conditions, but strong and pro- not feasible with this method and identification is typically longed perturbations can occur in disease conditions or limited to family or genus level [37]. Another consider- with antibiotics. At the species level there is enormous ation in 16S analyses is that most bacteria contain mul- inter-individual heterogeneity in gut microbiomes, which tiple copies of the 16S rRNA gene, which can lead to has hindered efforts for clearly defining a core micro- inaccurate quantitation of bacterial cells [38]. Additional biome shared between healthy individuals. It has been bias can be introduced in the amplification step, depend- suggested that the functional capacity of the microbiota, ing on the choice of primers. Despite these limitations, the as depicted by abundances of genes involved in metabolic low cost and high-throughput potential of this technique pathways, could constitute a metric better suited to define make it the most commonly used for initial descriptive a core healthy microbiota [19, 24]. Indeed, the basic cat- data. egories of metabolic pathways were more evenly repre- Metagenomic shotgun sequencing generates short sented across individuals as compared to bacterial reads representing the whole genomic content within an taxonomy [19]. It remains to be determined whether environmental sample and is considered less biased than this shared set of metabolic pathways is the major char- 16S rRNA gene amplicon sequencing, because it does acteristic of a healthy microbiota. not contain a PCR amplification step. However, this can result in contamination with human genomic DNA and Next generation sequencing methods in microbiome studies requires higher sequence coverage to detect bacterial Culturing of bacterial strains has been central to classical species of low abundance. This necessitates additional microbiology and has enabled the study of individual path- data storage, computing power, and more sophisticated ogens and some commensal bacteria. For most commensal analysis pipelines. Errors can also be introduced in the bacteria, culture methods had not been optimized for their downstream analysis at the step of genome assembly or in vitro isolation and study. With recent improvements in gene prediction [39]. Various bioinformatic tools have methodology, a large proportion of commensal bacteria is been developed for metagenome assembly, and data- now considered culturable [25, 26]. Culturomics is a bases have been established for gene