Gut bacteria affect the tumoral immune milieu: distorting the efficacy of immunotherapy or not？

Figures & data

Figure 1. Contributions of gut commensal bacteria and their metabolites to the host immune system. Based on the function of antigen-presenting cells, such as DCs, NK cells, and macrophages, commensal bacteria mediate the differentiation of naïve CD4 + T cells into different subgroups, such as T-bet+ Th1 cells, GATA3+ Th2 cells, RORγt+ Th17 cells, and FOXP3+ Tregs, which further contribute to different immune modulation responses, and the production of various cytokines, such as TGF-β, IFN-γ and ILs. Immune regulation can be mediated not only by bacteria but also by their metabolites, especially SCFAs and AHR ligands, exerting functions by binding GPCRs and AHR on the surface of epithelial cells and immune cells, respectively, which subsequently contribute to augmented epithelial barrier function and improved gut immune tolerance. Conversely, some immune cells and epithelial cells can also mediate the balance of bacteria by secreting antibacterial substances, such as B cells secreting IgA, Goblet cells secreting mucins and Paneth cells secreting antimicrobial peptides, etc. Overall, microbiota-immune cross-talk contributes to gut homeostasis by forming a relatively stable feedback loop. SCFAs, short-chain fatty acids; AHR, aromatic hydrocarbon receptor; GPCRs, G protein-coupled receptors; TCR, T cell receptor; PRR, pattern recognition receptor; DAMP, damage-associated molecular pattern; MHC-II, major histocompatibility complex II; B7, B7.1(CD80)/B7.2(CD86); DC, dendritic cell; NK, natural killer cell; NE, neutrophil; Treg, regulatory T cell; CTL, cytotoxic T lymphocyte; ILC, innate lymphoid cell; IFN-γ, interferon-γ; TGF-β, transforming growth factor; and IL, interleukin.

Figure 2. Potential mechanism that explains the anticancer or pro-cancer effects of some candidate ICI-therapy-associated bacteria by shaping the host immune status. Lactobacilli may upregulate the expression of MHC-II on DCs, enhance the activity of NK cells and macrophages, and improve Th1-mediated immune responses as well as increase the production of IFN-γ in tumors. The effects described above facilitate the anticancer potential of Lactobacilli. Bifidobacteria can improve the efficacy of anti-PD-L1 therapy by upregulating the expression of MHC-II on DCs, promoting Th1 polarization and CTL accumulation in the tumor microenvironments, and reducing the toxicity of anti-CTLA-4 therapy through enhanced Treg cell metabolism. Akkermansia muciniphila can enhance the efficacy of anti-PD-1 therapy in a manner dependent on the enhanced IL-12-dependent Th1-related immune response, along with increased levels of IFN-γ and TNF-α and decreased levels of IL-4 and IL-10. The results from a preclinical trial confirmed that Bacteroidetes can restore anti-CTLA-4 treatment efficacy by enhancing the IL-12-dependent Th1-related immune response, whereas these bacteria are associated with poor clinical outcomes of anti-CTLA-4 or anti-PD-1 therapy in human clinical trials. Fusobacterium nucleatum can promote tumor progression in gastrointestinal cancer and pancreatic cancer, and it is verified to be associated with reduced density of CD3 + T cells, exhaustion of NK cells, and augmentation of M2 polarization along with accumulation of MDSCs in tumor microenvironments. These effects may be closely linked with their colonization in tumors.

Table 1. Effects of potential immune-associated bacteria on the host immune system.

Bacteria	Model	Effects on the immune system	Refs
Lactobacillus reuteri	Treg-deficient mice	Decreased levels of IFN-γ and IL-4; Inhibition of Th1- or Th2- responses.	^Citation74
	Germ-free mice and mice without CD8^+CD4^+ double-positive intraepithelial lymphocytes	Induction of CD8^+CD4^+ double-positive intraepithelial lymphocytes cells.	^Citation76
	Breast cancer-bearing mice	Induction of CD4^+CD25^+ Treg cells; Suppression of mammary tumorigenesis.	^Citation109
Lactobacillus acidophilus	Breast cancer-bearing mice	Increased levels of IFN-γ, IL-4 and TGF-β; Establishment of a Th1 protective pattern.	^Citation80
Lactobacillus brevis	Breast cancer-bearing mice	Increased levels of IFN-γ, TNF-α, IL-2, IL-17; Increased cytotoxic activity of NK cells.	^Citation81,Citation82
Lactobacillus casei	Colorectal cancer-bearing mice	Reduced level of IL-22; Increased levels of IL-6, IL-17, IL-10, TGF-β; Mediation of Treg-to-Th17-biased immune response; Protection against dysbacteriosis.	^Citation79,Citation110
Lactobacillus rhamnosus	Mice with depletion of EGFR in intestinal epithelial cells	Promotion of epithelial cell proliferation, differentiation and tight junction formation; Regulation of the differentiation of T helper cells, Treg cells, and B cells.	^Citation111
Bifidobacterium spp.	Melanoma-bearing mice and melanoma-bearing Foxp3-DTR mice; Anti-CTLA-4 mAb	Amelioration of intestinal immunopathology without distorting antitumor effects of anti-CTLA-4 mAb; Decreased levels of IL-6.	^Citation88
Bifidobacterium spp.	Melanoma-bearing mice; Anti-PD-L1 mAb	Upregulation of MHC-II by DCs; Accumulation of CD8 + T cells in tumors; Increased levels of IFN-γ in tumors.	^Citation52
Bifidobacterium longum	Healthy adult mice	Upregulation of IL-4, IL-6, IL-10, IFN-γ and TGF-β in ileal Peyer’s patches	^Citation112
	Mice with gliadin-induced enteropathy	Reduction in CD4^+Foxp3^+ cells. Increases in CD8^+ T cell populations; Upregulation of NF-kB and IL-10 expression; Decrease in TNF-α production.	^Citation113
	Healthy infant mice	Increase in IFN-γ-secreting cells and ratio of IFN-γ-secreting to IL-4-secreting cells; Strengthened Th1-related immune response.	^Citation85
Bifidobacterium adolescentis	Healthy conventional mice and germ-free mice	Increased number of Th17 cells in the small intestine.	^Citation86
Akkermansia muciniphila	Epithelial tumor patients Sarcoma-bearing mice Anti-PD-1 mAb	Beneficial clinical responses to anti-PD-1 mAb in patients; IL-12-dependent recruitment of Th1 cells into tumor beds; Increased levels of IFN-γ and TNF-α and decreased levels of IL-4 and IL-10.	^Citation21
Bacteroidetes	Melanoma patients Melanoma-bearing mice Anti-PD-1 mAb	High number of Tregs and MDSCs; Blunted cytokine response in melanoma patients; Increased frequency of Th17 cells and Tregs in model mice.	^Citation20
	Melanoma patients Anti-CTLA-4 mb	Poor response to anti-CTLA-4 mAb; High number of α4^+β7^+ T cells in the periphery.	^Citation22
Bacteroides Fragilis/Bacteroides thetaiotaomicron	Sarcoma-bearing mice Anti-CTLA-4 mAb	Accumulation of CD11b^+ DCs in the lamina propria IL-12-dependent Th1 immune response in tumor-draining lymph nodes.	^Citation103
Fusobacterium nucleatum	Colorectal cancer patients	Inverse correlation with CD3^+ T cell density in tumors.	^Citation104
	Apc^Min/+ mice	Accumulation of MDSCs and M2-like TAMs.	^Citation107

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