Historical accounts linking cancer and microbes date as early as four millennia ago. Post 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 pyogenesinfections. Over the next century, the role of bacteria in carcinogenesis and cancer therapy was discounted due to poor reproducibility, erroneous microbiological claims, and severe toxicity in patients. However, these provided some of the first crude demonstrations of cancer immunotherapy. Contemporaneously, the viral theory of cancer began to flourish, spurred by the 1911 discovery of Rous Sarcoma Virus (RSV), which transformed benign tissue into malignant tumors in domestic fowl. The subsequent decades-long search to find a virus behind every human cancer ultimately failed, and many cancers have been fundamentally 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 the evidence for these claims in light of modern cancer biology and immunology, and delineates the roles of microbes in cancer by examining recent advances in proposed mechanisms, diagnostics, endogenous modulation approaches, and exogenous therapeutic strategies.
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 have demonstrated powerful effects on innate and adaptive immunity by modulating primary and secondary lymphoid tissue activities against cancer and tumor immunosurveillance. Many of these pathways invoke Toll-like receptor (TLR)-initiated cytokine signaling, but microbial metabolic effects in dietary energy harvest and short-chain fatty acid production, 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 also suggests the existence and functional activity of intratumoral bacteria, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data on them in ~10 cancer types. Preliminary studies also suggest that fungi and bacteriophages contribute to gastrointestinal cancers. However, the estimated cellular abundances of intratumoral microbes 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 yet to broadly materialize into commercialized therapies. Synthetic biology approaches are also gaining traction, however, with engineered bacterial cancer therapies in preclinical and clinical trial settings.
A better understanding of the roles of microbes in cancer has the opportunity to improve each stage of the cancer care cycle, but major challenges must be surmounted. 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 (TCGA)’s and International Cancer Genome Consortium (ICGC)’s roles 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.
Microbial roles in cancer formation, diagnosis, prognosis, and treatment have been disputed for centuries. Recent studies have provocatively claimed that bacteria, viruses, and/or fungi are pervasive among cancers, key actors in cancer immunotherapy, and engineerable to treat metastases. Despite these findings, the number of microbes known to directly cause carcinogenesis remains small. Critically evaluating and building frameworks for such evidence in light of modern cancer biology is an important task. In this Review, we delineate between causal and complicit roles of microbes in cancer and trace common themes of their influence through the host’s immune system, herein defined as the immuno-oncology-microbiome (IOM) axis. We further review evidence for intratumoral microbes and approaches that manipulate the host’s gut or tumor microbiome while projecting the next phase of experimental discovery.
The histories of cancer and human microbiota are intimately interwoven. Writings as early as 1550 BCE in the Ebers Papyrus, attributed to the Egyptian physician Imhotep (c 2600 BCE), suggest a crude treatment for tumors (swellings) involving application of a poultice to the site followed by an incision, causing an infection (1, 2). In the 13th century, Peregrine Laziosi described spontaneous regression of his septic, ulcerative tibial bone malignancy that would have required amputation (2), for which he was canonized in 1726. After establishment of the germ theory of infectious disease, Wilhelm Busch and Friedrich Fehleisen independently reported in the late 1800s that Streptococcus pyogenes infections were associated with spontaneous tumor regressions in several patients (3, 4). Shortly thereafter, William Coley started testing a highly contentious and sometimes lethal vaccine of live or heat-killed Streptococcus and Serratia species on terminal cancer patients, which was only later shown to yield >10-year disease-free survival in ~30% of them (60 of 210 total), representing the first intentional demonstration of immunotherapy (5). Contemporaneously, Thomas Glover and Virginia Livingston-Wheeler claimed, controversially, that bacteria were cultivable from tumors and that bacterial vaccines were effective against tumors, and suggested a universal bacterial origin of cancer (6, 7). These early treatment approaches and theories were fraught with error: Livingston-Wheeler’s bacterial “cause” of cancer, Progenitor cryptocides, turned out to be the skin commensal Staphylococcus epidermidis (a frequent contaminant), and Glover’s findings were not reproducible by researchers at the National Institutes of Health (7). With no mechanistic evidence, irreproducible results, and hazardous therapies, the bacterial theory of cancer was dismissed.
The viral theory of cancer gained traction after Peyton Rous’s 1911 discovery of a transmissible oncogenic virus in chickens (8). The subsequent decades-long search to find a virus behind every cancer linked Epstein-Barr, human papilloma, and hepatitis viruses to carcinogenesis (9) but failed to find a viral cause for most human cancers, and the theory was overtaken by the somatic mutation hypothesis.
Now, after decades of research thoughtfully characterizing the hallmarks of human cancer through somatic mutations and other host-centric perspectives (10, 11), the field is encountering nuanced claims that microbes may play a broad role in cancer diagnosis, pathogenesis, and treatment (12–26). This reappraisal stems from greater appreciation of the number of microbes that inhabit the human body (roughly equal to the number of human cells), their gene count that exceeds the human genome’s gene count by ~100-fold and enables diverse metabolic programming, and their effects on host immune system development and activity, including antitumor immunosurveillance (27–31). Although most proposed cancer-microbe relationships focus on gut microbiota (30, 32, 33), recent studies also contentiously suggest the existence, metabolic activity, and functional importance of intratumoral microbiota using a combination of imaging, sequencing, and cultivation techniques, and genetically-engineered and germ-free mouse models (12–14, 18–20, 23, 34). These studies raise many questions about microbes and cancer. How should microbes be viewed in light of known host-centric cancer characteristics? To what extent are microbes causal agents, complicit actors, or passive bystanders? If intratumoral microbes exist, do they have therapeutic implications? What role do microbes play in patient management? With these questions in mind, this Review aims to critically evaluate the known roles of microbes in cancer, and to outline the next steps for evaluating their clinical utility.
Overview of the cancer microbiome
Of the estimated ~1012 distinct microbial species on earth (35), just 11 are labeled human carcinogens, or “oncomicrobes,” by the International Association for Cancer Registries (IACR) (36). These oncomicrobes cause an estimated 2.2 million cases per year (~13% of global cancer cases), and their epidemiology, molecular mechanisms, and clinical studies have been extensively reviewed (36). Strong experimental evidence suggests that additional microbes initiate cancer through genotoxin-mediated mutagenesis; in particular, colibactin (a DNA alkylator), cytolethal distending toxin (CDT; direct DNAse activity), and Bacteroides fragilis toxin (Bft; ROS producer) cause mutational signatures found in colorectal, head and neck, and urinary tract cancers (22, 37–41). Experimental evidence also implicates several microbes with virulence factors that amplify tumorigenesis via E-cadherin/Wnt/β-Catenin signaling, including FadA from Fusobacterium nucleatum and AvrA from several Salmonella strains (42, 43). A few dozen microbial species can thus directly cause cancer, based on current epidemiological and experimental evidence.
Increasing evidence suggests an important additional category of “complicit” microbes and microbial functions that promote carcinogenesis but are insufficient to cause cancer (18, 20, 25, 38, 44–47). This category encapsulates many immunomodulatory functions of microbiota and their bioactive metabolites in tumor development, and may be linked to the immune system’s role in solid tumorigenesis; the immune system rarely initiates the incipient lesion but can facilitate progression through tumor-stroma feedback loops, inflammation, or dysfunctional immunosurveillance (11). One example is that common p53 mutations are only carcinogenic in the presence of microbially-produced gallic acid and protective otherwise in the gut, both in vivo and in organoids, suggesting a microbiome-functional genomic interaction (44). A second is microbially-produced secondary bile acids, which reduce hepatic sinusoidal CXCL16 expression (the sole ligand for CXCR6) and prevent CXCR6+ natural killer T (NKT) cell aggregation and liver cancer immunosurveillance — this carcinogenic effect is eliminated by vancomycin treatment (45). A third comes from the inability of Kras mutation and p53 loss to produce lung cancer in germ-free or antibiotic-treated mice: commensal lung microbiota promote expansion and activation of γδ T cells, which drives tumor-promoting inflammation via local IL-17 and IL-23 release (18). These examples illustrate how microbes or microbial functions can be complicit in cancer rather than directly causal.
In contrast to the few bona fide oncomicrobes, the many “complicit” microbes and their functions are broad and under-studied. Complicit microbes require mediators to promote tumor development, but modulate tumor progression and therapeutic efficacy locally or from a distance. Complicit microbes are also least understood, requiring comprehension and integration of host and microbial biology, so we emphasize them in this Review. Together with known causal mechanisms, the diversity of these “complicit” mechanisms and their relationships to host-centric cancer hallmarks (10, 11) are notable (Fig. 1), but they will require more rigorous experimentation and cross-cohort validation to establish clinical prevalence and utility.
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