IDDF2024-ABS-0383 Lactobacillus intestinalis facilitates tumor-derived CCL5 to recruit dendritic cell and suppress colorectal tumorigenesis

<h3>Background</h3> Colorectal cancer (CRC) is one of the most common malignancies worldwide. The intestinal microbiota plays a crucial role in regulating the tumor microenvironment (TME) of CRC. Recent studies have identified various microorganisms that inhibit tumorigenesis and progression; however, the intricate mechanisms underlying the interaction between gut microbiota and the TME require further elucidation. Previous research has shown that <i>Lactobacillus intestinalis</i> (<i>L. intestinalis</i>) can inhibit colitis, but its role in CRC remains unclear. <h3>Methods</h3> This study aimed to evaluate the anti-tumor effects of <i>L. intestinalis</i> using an AOM/DSS-induced CRC model and the <i>Apc</i>^min/+ spontaneous colorectal adenoma model. Immune infiltration profiles were characterized using multi-color flow cytometry. The involvement of the NOD1/NF-κB pathway was confirmed using the NOD1 receptor-specific inhibitor ML-130 and the NF-κB signaling pathway inhibitor BAY11-7082. Fecal samples and tumor tissues from patients were collected for genome DNA and mRNA profiling. <h3>Results</h3> The abundance of <i>L. intestinalis</i> was decreased in fecal samples from CRC and CRA patients. Supplementation with <i>L. intestinalis</i> inhibited tumorigenesis in both murine models and increased the infiltration of total immune cells, particularly dendritic cells (DCs), in the TME. Co-culture of MC38 cells with <i>L. intestinalis</i> increased the migration ability of DCs. Mechanistically, <i>L. intestinalis</i> upregulated the expression of <i>Ccl5</i> in MC38 cells. Knockdown of <i>Ccl5</i> reduced the capacity of MC38 cells to attract DC migration when co-cultured with <i>L. intestinalis</i>. Moreover, ML-130 and BAY11-7082 significantly attenuated the <i>L. intestinalis</i>-induced CCL5 secretion, indicating the involvement of the NOD1/NF-κB pathway. In CRC patient tumor sites, the abundance of <i>L. intestinalis</i> positively correlated with the expression levels of <i>CCL5</i>, <i>ITGAX</i>, and <i>NOD1</i> genes. <h3>Conclusions</h3> This study provides the first evidence of the <i>in vivo</i> anti-tumor activity of <i>L. intestinalis</i>, revealing its mechanism of suppressing tumorigenesis by stimulating tumor cells to secrete CCL5 and recruiting DCs into the TME via the NOD1/NF-κB pathway. These findings highlight the significance of tumor cell responses to microbial signals within the tumor immune microenvironment, offering broader insights into the microbe-tumor-TME interaction.