Abstract
The involvement of gut microbiota in T-cell trafficking into tumor tissue of colorectal cancer (CRC) remains to be further elucidated. The current study aimed to evaluate the expression of major cytotoxic T-cell trafficking chemokines (CTTCs) and chemokine-associated microbiota profiles in both tumor and adjacent normal tissues during CRC progression. We analyzed the expression of chemokine C-X-C motif ligands 9, 10, and 11 (CXCL9, CXCL10, and CXCL11), and C-C motif ligand 5 (CCL5), characterized gut mucosa-associated microbiota (MAM), and investigated their correlations in CRC patients. Our results showed that the expression of CXCL9, CXCL10, and CXCL11 was significantly higher in tumor than in adjacent normal tissues in 136 CRC patients. Notably, the high expression of CXCL9 in tumor tissues was associated with enhanced CD8+ T-cell infiltration and improved survival. Moreover, the MAM in tumor tissues showed reduction of microbial diversity and increase of oral bacteria. Microbial network analysis identified differences in microbial composition and structure between tumor and adjacent normal tissues. In addition, stronger associations between oral bacteria and other gut microbes were observed. Furthermore, the correlation analysis between the defined MAM and individual CTTCs showed that the CTTCs’ correlated operational taxonomic units (OTUs) in tumor and adjacent normal tissues rarely overlap with each other. Notably, all the enriched OTUs were positively correlated with the CTTCs in either tumor or adjacent normal tissues. Our findings demonstrated stronger interactions between oral bacteria and gut microbes, and a shifted correlation pattern between MAM and major CTTCs in tumor tissues, underlining possible mechanisms of gut microbiota–host interaction in CRC.
Highlights
Colorectal cancer (CRC) accounts for the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide [1]
The expression of CXCL9, CXCL10, and CXCL11 except for C-C motif ligand 5 (CCL5) was significantly higher in the tumor compared with the adjacent normal tissues (Figures 1A–D; p = 0.0707, p = 0.0001, p < 0.0001, and p = 0.4207)
We aimed to explore the chemotactic factors associated with colorectal cancer (CRC) prognosis and to profile mucosa-associated microbiota (MAM) of CRC patients and to investigate the relationship between mucosae microbiota and chemokines involved in cytotoxic T cells (CTCs) recruitment during CRC progression
Summary
Colorectal cancer (CRC) accounts for the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide [1]. High infiltration with cytotoxic T cells (CTCs) correlates with improved relapse-free and overall survival (OS) in patients with CRC [2,3,4]. It has been reported that CTCs with higher CXCR3 expression can be recruited to the tumor site by ligands, including CXCL9, CXCL10, and CXCL11, which are known as IFNg-inducible chemokines [12, 13]. Studies have identified CCL5 and its receptor (C-C motif) receptor 5 (CCR5) as another critical component of T-cell chemotaxis that is closely associated with CTC infiltration and better survival [12]. Expression of specific chemokines in tumors could be potentially correlated with the presence of CTCs, which might serve as useful targets for anti-cancer therapies
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