Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes

Abstract

Despite the promising advances in novel cancer therapy such as immune checkpoint inhibitors (ICIs), limitations including therapeutic resistance and toxicity remain. In recent years, the relationship between gut microbiota and cancer has been extensively studied. Accumulating evidence reveals the role of microbiota in defining cancer therapeutic efficacy and toxicity. Unlike host genetics, microbiota can be easily modified via multiple strategies, including faecal microbiota transplantation (FMT), probiotics and antibiotics. Preclinical studies have identified the mechanisms on how microbes influence cancer treatment outcomes. Clinical trials have also demonstrated the potential of microbiota modulation in cancer treatments. Herein, we review the mechanistic insights of gut microbial interactions with chemotherapy and ICIs, particularly focusing on the interplay between gut bacteria and the pharmacokinetics (eg, metabolism, enzymatic degradation) or pharmacodynamics (eg, immunomodulation) of cancer treatment. The translational potential of basic findings in clinical settings is then explored, including using microbes as predictive biomarkers and microbial modulation by antibiotics, probiotics, prebiotics, dietary modulations and FMT. We further discuss the current limitations of gut microbiota modulation in patients with cancer and suggest essential directions for future study. In the era of personalised medicine, it is crucial to understand the microbiota and its interactions with cancer. Manipulating the gut microbiota to augment cancer therapeutic responses can provide new insights into cancer treatment.

Keywords: cancer; chemotherapy; enteric bacterial microflora; immunotherapy.

Figure 1

Mechanisms of microbiota modulation on chemotherapy response. (A) Irinotecan (CPT-11) is converted to SN-38 to elicit its cytotoxic effect after injection into the body. SN-38 is then detoxified by UGT in the liver to become SN-38G and excreted into the GI tract. The gut bacteria can reactivate and convert SN-38G back to SN-38, causing toxicity to intestinal cells. (B) Bacterial ribonucleotide metabolism activates fluoropyrimidine prodrugs into activated forms for cytotoxic effects. Vitamin B₆ and B₉ production is required for the metabolism. (C) Intratumoral Gammaproteobacteria with long isoform of cytidine deaminase can inactivate gemcitabine, leading to chemoresistance. (D) CTX increases intestinal permeability to promote Enterococcus hirae translocation into the spleen to increase pathogenic Th17 cells and intratumoral CD8+/CD4+ T cells ratio. (E) Gut microbes can prime tumour-infiltrating myeloid cells via MYD88-dependent pathway for ROS production in response to chemotherapeutic drugs. (F) Antigenicity from oxaliplatin-induced apoptosis of epithelial cells together with immunogenic bacteria, including non-enterotoxigenic Bacteroides fragilis and Erysipelotrichaceae, can stimulate the differentiation of migratory DCs to TFH cells for B cell activation. (G) Microbial metabolites such as butyrate can activate cytotoxic CD8+ T cells to enhance the efficacy of oxaliplatin. (H) Fusobacterium nucleatum can activate TLR4/MYD88-dependent pathway to inhibit certain miRNAs and switch tumour cells from apoptosis to autophagy, leading to chemoresistance. Figure created with BioRender.com. CPT-11, irinotecan; CTL, cytotoxic T lymphocyte; CTX, cyclophosphamide; DCs, dendritic cells; FdUMP, 5-fluorodeoxyuridine 5′-monophosphate; FUMP, 5-fluorouridine 5′-monophosphate; FUTP, 5-fluorouridine 5′-triphosphate; GzmB, Granzyme B; IFN-γ, interferon-γ; IL, interleukin; miRNA, microRNA; MYD88, myeloid differentiation primary response 88; NK, natural killer; PFN, perforin; pTH17 cells, pathogenic T helper 17 cells; ROS, reactive oxygen species; SN-38, 7-ethyl-10-hydroxycamptothecin; TFH, follicular T helper; TLR4, toll-like receptor-4; TNF-α, tumour necrosis factor alpha; Treg, T regulatory cells; UGT, uridine diphosphate glucuronosyltransferase.

Figure 2

Mechanisms of microbiota modulation on immunotherapy response. Microbes–immunotherapy interactions could be categorised by the ‘TIME’ mechanistic framework: T cell mediation, Innate immunity, Metabolites, molecular mimicry, and Epithelial injury. (A) Bacteria such as Bacteroides, Burkholderiales and Bifidobacterium could enhance anticancer T cell immunity mediated by DCs for immunotherapy potentiation. (B) NK cells and proinflammatory M1 macrophages are the main contributors of innate immunity against cancer. Bifidobacterium could activate NK cells to combat cancers, while intratumoral microbiota ablation in PDAC could reprogramme M2 macrophages to M1 macrophages and reduce myeloid-derived suppressor cells. Altogether they increase the sensitivity of tumours to immunotherapy. (C) Bifidobacterium pseudolongum and Akkermansia muciniphila could secrete metabolite inosine. Inosine activates Th1 cells via adenosine 2A receptor costimulated by DCs. Other bacteria could improve ICI anticancer response via molecular mimicry. Bifidobacterium breve and Enterococcus hirae-infecting bacteriophage have SVY and TMP antigens, respectively, which are highly similar to tumour neoantigens. This leads to cross-reactivity of cytotoxic T cells against tumour cells. (D) Epithelial injury and immunogenic bacteria stimulate DCs for anticancer immunity. Figure created with BioRender.com. DCs, dendritic cells; ICI, immune checkpoint inhibitor; IL, interleukin; MDSC, myeloid-derived suppressor cells; NK, natural killer; PD-1, programmed cell death protein-1; PDAC, pancreatic ductal adenocarcinoma; SVY, SVYRYYGL; TFH, follicular T helper; Th, T helper; TMP, tape measure protein.