Fig. 2
Potential Mechanisms for Microbiota-Mediated Immunomodulation in Tumor (see attached file). Gut microflora can exert an impact on tumor immunity both locally and systemically. Locally, Fusobacterium may act on CRC cells via TLR4/MYD88 signaling pathway. The activation of NF-kB promoted the transcription of pro-inflammatory cytokines such as TNF-α and IL-6, leading to the accumulation of immunosuppressive myeloid cells in TME. Systemically, bacterial flagellin accelerated distal malignant progression via TLR5 signaling, resulting in increased systemic IL-6 and subsequent more γδT cells to produce immunosuppressive galectin-1. Furthermore, the enterohepatic circulation enabled microbiota-derived PAMP and metabolites to play a role in HCC. On one hand, in the context of HCC, there is a significant increase in portal and systemic LPS, owing to dysbiosis and increased gut permeability. Elevated LPS activated NF-κB in HSC, inducing production of inflammatory chemokines. These cytokines could enhance migration of macrophages and MDSCs to the liver. Similarly, gut-derived LTA induced the expression of COX2 to promote local production of PGE2. Then PGE2 suppressed the antitumor response through the PTGER4 receptor on immune cells, manifested as decreased production of IFN-γ and TNF-α, reduced CD103+DC and increased CD4+FOXP3+Treg. On the other hand, depletion of gram-positive bacteria involved in primary-to-secondary bile acid conversion increased the expression of CXCL16. Upregulation of CXCL16 induced accumulation and activation of CXCR6+NKT cells, which suppressed liver tumor growth. In addition, intestinal microbiota could also control the immune tone of secondary lymphoid organs via bacterial translocation. The translocation of selected Gram-positive bacterial species into spleen is indispensable for CTX-driven accumulation of pTh17 cells, which increased systemic CD8+T cells and intratumoral CTL/Treg ratio. BA: bile acid; CRC: colorectal cancer; TLR: Toll-like receptor; TME: tumor microenvironment; PAMP: pathogen-associated molecule pattern; HCC: hepatocellular carcinoma; LPS: lipopolysaccharide; MDSC: myeloid-derived suppressor cells; LTA: lipoteichoic acid; HSC: hepatic stellate cell; HSEC: hepatic sinusoidal endothelial cell; SCFA: short-chain fatty acids