Modulating the microbiome to improve therapeutic response in cancer

Summary

Although novel therapies, including immunotherapy, have dramatically improved outcomes for many patients with cancer, overall outcomes are heterogeneous and existing biomarkers do not reliably predict response. To date, predictors of response to cancer therapy have largely focused on tumour-intrinsic features; however, there is growing evidence that other host factors (eg, host genomics and the microbiome) can substantially affect therapeutic response. The microbiome, which refers to microbiota within a host and their collective genomes, is becoming increasingly recognised for its influence on host immunity, as well as therapeutic responses to cancer treatment. Importantly, microbiota can be modified via several different strategies, affording new angles in cancer treatment to improve outcomes. In this Review, we examine the evidence on the role of the microbiome in cancer and therapeutic response, factors that influence and shape host microbiota, strategies to modulate the microbiome, and present key unanswered questions to be addressed in ongoing and future research.

Introduction

The development of novel therapies such as immune checkpoint inhibitors has resulted in dramatic improvements in the outcomes of many patients with cancer. However, outcomes are heterogeneous, with some patients achieving dramatic durable complete remissions, and others deriving no benefit at all. Beyond tumour-intrinsic features that might predict response and drive resistance, there is increasing evidence that host (ie, patient) factors, including the microbiota, might influence response to therapy.1, 2, 3, 4, 5, 6

The human microbiota is comprised of complex communities of trillions of microbes that live on and inside humans. These commensal microorganisms have co-evolved with humans to have several functions that benefit human health, including harvesting otherwise inaccessible nutrients from the diet, maintaining integrity of mucosal barriers, and contributing to immune system development and homoeostasis.7, 8

Our understanding of the microbiome has grown exponentially in the past decade with the development of high-throughput sequencing approaches.7, 8 The most common component of the human microbiome that is sequenced is the small 30S ribosome subunit, which is unique to prokaryotes and has regions that vary greatly between different species of bacteria (16S sequencing). This technique can be used to quantify alpha diversity (the number of distinct species present and whether distinct species are evenly represented) and beta diversity (differences in taxonomic abundance profiles between different samples), as well as differential abundance of specific bacterial taxa. By contrast, whole-genome or metagenomic sequencing involves sequencing the entire genomes of all microbes (including viruses, fungi, protozoa, archaea) in a given sample. Metagenomic sequencing has the added advantage of deeper resolution and allows for imputation of function, but at a substantially higher cost in terms of both time and money; however, as with all omics-based profiling, the cost is decreasing and resolution increasing. As such, some components of the human microbiota, such as viruses and fungi, as well as archaea, protozoa, and other microbes, have been less well studied to date than bacteria. Characterisation of these other components of the human microbiota is an area of deep investigation and it is likely that a growing role for these non-bacterial counterparts will be uncovered in the near future. Nonetheless, complexities exist with the characterisation of such components given the vast diversity of virotypes (and viral genomes) that are present in the microbiome, among other variables. Notably, the composition of these other microbial components might directly or indirectly affect the composition of the gut bacterial components; thus, as the field moves forward, these potential interactions must be taken into consideration.

Although novel sequencing techniques have added substantially to our understanding of the human microbiome, we cannot fully understand function and mechanism from computational analysis alone. There has been renewed interest in the field of culturomics—a high-throughput method of culturing microbial species that were otherwise previously deemed difficult or impossible to culture. Culturing bacteria in this way will enable us to study the bacteria themselves rather than their genomes only and thus will help elucidate certain mechanisms of the microbiome in a way that using computational methods alone will not.9, 10

As our understanding of the microbiota grows, it is becoming increasing clear that the microbiota plays a key role in human health and disease. Disruption of the gut microbiome (dysbiosis) has been implicated in a range of human diseases, including gastrointestinal, autoimmune, neurological, and metabolic diseases.⁸ For cancer, specific bacterial and viral infections have been implicated in carcinogenesis11, 12, 13, 14, 15, 16 and have also been associated with treatment-related toxicity to cancer therapy.3, 17, 18, 19 Importantly, microbiota (specifically within the gut) have been shown to affect immune responses, with studies reporting strong associations between gut microbiota and response to immune checkpoint blockade and other therapies in human cohorts and murine models.1, 2, 4, 5, 20, 21, 22, 23 There is also evidence from preclinical models that successful modulation of the gut microbiota can enhance therapeutic response.

Accordingly, strategies to modulate the microbiome are being used and developed for various human diseases, including cancer. Such strategies include the use of faecal microbiota transplant, which is a safe and effective approved therapy for recurrent Clostridium difficile,²⁴ and is being used experimentally to treat inflammatory bowel disease,²⁵ metabolic diseases,²⁶ and even cancer (table 1). Additional strategies to manipulate the microbiome are also under investigation (including probiotic administration and dietary intervention) in multiple diseases, although vast heterogeneity in study design presents a challenge in interpreting the success of these approaches.

In this Review, we assess the evidence for the role of the microbiota in the therapeutic response of cancer, outline the determinants of the microbiota and potential strategies and considerations for microbiota modulation, as well as highlight the complexities with this approach, and a potential path forward for cancer treatment.