The microbiome and human cancer
Authors: Sepich-Poore Gregory D. , Zitvogel Laurence , Straussman Ravid , Hasty Jeff , Wargo Jennifer A. , Knight Rob 
Published: March 2021

BACKGROUND

Historical accounts linking cancer and microbes date as early as four millennia ago. After establishment of the germ theory of infectious diseases, clinical research of microbial influences on cancer began in 1868, when William Busch reported spontaneous tumor regressions in patients with
Streptococcus pyogenes
infections. Over the next century, poor reproducibility, erroneous microbiological claims, and severe toxicity led many to discount the role of bacteria in carcinogenesis and cancer therapy. However, these studies provided the first crude demonstrations of cancer immunotherapy. Contemporaneously, the viral theory of cancer flourished, spurred by the 1911 discovery of Rous sarcoma virus, which transformed benign tissue into malignant tumors in chickens. The decades-long search to find viruses behind every human cancer ultimately failed, and many cancers have been linked to somatic mutations. Now the field is encountering intriguing claims of the importance of microbes, including bacteria and fungi, in cancer and cancer therapy. This Review critically evaluates this evidence in light of modern cancer biology and immunology, delineating roles for microbes in cancer by examining advances in proposed mechanisms, diagnostics, and modulation strategies.

ADVANCES
Few microbes directly cause cancer, but many seem complicit in its growth, often acting through the host’s immune system; conversely, several have immunostimulatory properties. Mechanistic analyses of gut microbiota–immune system interactions reveal powerful effects on antitumor immunity by modulating primary and secondary lymphoid tissue activities. Many of these pathways invoke Toll-like receptor–initiated cytokine signaling, but microbial metabolic effects and antigenic mimicry with cancer cells are also important. In preclinical models, microbial metabolites also regulate phenotypes of tumor somatic mutations and modulate immune checkpoint inhibitor efficacy.
Emerging evidence suggests that intratumoral bacteria exist and are active, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data in ~10 cancer types. Preliminary studies further suggest that fungi and bacteriophages contribute to gastrointestinal cancers. However, the abundance of intratumoral microbial cells is low relative to cancer cells, and knowledge of their functional repertoire and potency remains limited. Further validation of their prevalence and impact is needed in diverse cohorts and therapeutic contexts.
The immunomodulatory effects of host microbiota have reinvigorated efforts to change their composition as a form of immunotherapy. Despite extensive preclinical evidence, translation of microbiota modulation approaches into humans has not yet materialized into commercialized therapies. Synthetic biology approaches are also gaining traction, with engineered bacterial cancer therapies in preclinical and clinical trial settings.

OUTLOOK
A better understanding of the roles of microbes in cancer provides an opportunity to improve each stage of the cancer care cycle, but major challenges remain. Concerted efforts to characterize cancer-associated microbiota among tumor, stool, and blood samples with gold-standard contamination controls would tremendously aid this progress. This would be analogous to The Cancer Genome Atlas’s role in characterizing the cancer somatic mutation landscape. Large-scale clinical trials are currently testing the efficacy of microbiota modulation approaches, ranging from dietary modifications to intratumorally injected, engineered bacteria. These bacterial cancer therapies, if safe and effective, could tremendously expand the cancer therapy armamentarium. Altogether, integrating the host-centric and microbial viewpoints of cancer may improve patient outcomes while providing a nuanced understanding of cancer-host-microbial evolution.

Opportunities for microbes to affect cancer care.

Diagnosis: Cancer-specific, blood-borne microbial DNA may complement cell-free tumor DNA (ctDNA). Prognosis: Gut and intratumoral microbiota may stratify patient outcomes (NR, nonresponder; R, responder; TME, tumor microenvironment). Therapy: Intratumor injection of CD47 nanobody (CD47nb)–producing
Escherichia coli
may create systemic antitumor immunity by enhancing dendritic cell (DC) phagocytosis, lymph node (LN) antigen (Ag) presentation, and cytotoxic T lymphocyte (CTL) activity.