Colibactin‐positive Escherichia coli induce a procarcinogenic immune environment leading to immunotherapy resistance in colorectal cancer

Abstract

Colibactin‐producing E. coli (CoPEC) are frequently detected in colorectal cancer (CRC) and exhibit procarcinogenic properties. Because increasing evidence show the role of immune environment and especially of antitumor T‐cells in CRC development, we investigated the impact of CoPEC on these cells in human CRC and in the APCMin/+ mice colon. T‐cell density was evaluated by immunohistochemistry in human tumors known for their CoPEC status. APCmin/+ mice were chronically infected with a CoPEC strain (11G5). Immune cells (neutrophils and T‐cell populations) were then quantified by immunofluorescent staining of the colon. The quantification of lymphoid populations was also performed in the mesenteric lymph nodes (MLNs). Here, we show that the colonization of CRC patients by CoPEC is associated with a decrease of tumor‐infiltrating T lymphocytes (CD3+ T‐cells). Similarly, we demonstrated, in mice, that CoPEC chronic infection decreases CD3+ and CD8+ T‐cells and increases colonic inflammation. In addition, we noticed a significant decrease in antitumor T‐cells in the MLNs of CoPEC‐infected mice compared to that of controls. Moreover, we show that CoPEC infection decreases the antimouse PD‐1 immunotherapy efficacy in MC38 tumor model. Our findings suggest that CoPEC could promote a procarcinogenic immune environment through impairment of antitumor T‐cell response, leading to tumoral resistance to immunotherapy. CoPEC could thus be a new biomarker predicting the anti‐PD‐1 response in CRC.

Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment

“…Decreased tumor-infiltrating lymphocytes (TILs) in the invasive CRC margin is associated with pks + E. coli ( 101 ). Moreover, APC Min/+ mice exposed to colibactin-producing E. coli exhibit more polyps and decreased CD3 + CD8 + T-cells than noninfected animals or infected with pks- lacking E. coli strains, suggesting colibactin induces a carcinogenic microenvironment ( 101 ).…”

Shining a Light on Colibactin Biology

“…While colibactin can directly promote oncogenic transformation by DNA alkylation and subsequent mutagenesis in epithelial cells [ 6 , 9 , 23 , 29 ], its role in CRC progression extends beyond these activities by helping to establish a pro-carcinogenic environment supporting tumor growth [ 62 , 63 , 64 ]. After pks -induced DNA damage, cells may undergo apoptosis, transformation, or senescence.…”

“…These changes may occur near cells that have acquired pks -generated mutations in the APC or p53 pathways after colibactin exposure [ 29 ], further promoting unrestricted growth and tumor proliferation. A recent study demonstrated that the pks + E. coli strain 11G5 translocates to mesenteric lymph nodes in Apc Min/+ mice, with a concomitant reduction of some cytotoxic T cell lineages and an increase in regulatory T cells within infected lymph nodes [ 64 ]. Furthermore, levels of cytotoxic T cells are reduced within the colonic mucosa of 11G5-colonized mice and invasive margins from tumor biopsies from CRC patients colonized by pks + E. coli [ 64 ], suggesting that colibactin-producing microbes may create a pro-carcinogenic environment within the gut by modulating immune cell activity.…”

“…A recent study demonstrated that the pks + E. coli strain 11G5 translocates to mesenteric lymph nodes in Apc Min/+ mice, with a concomitant reduction of some cytotoxic T cell lineages and an increase in regulatory T cells within infected lymph nodes [ 64 ]. Furthermore, levels of cytotoxic T cells are reduced within the colonic mucosa of 11G5-colonized mice and invasive margins from tumor biopsies from CRC patients colonized by pks + E. coli [ 64 ], suggesting that colibactin-producing microbes may create a pro-carcinogenic environment within the gut by modulating immune cell activity. Collectively, these observations suggest that colibactin-producing E. coli may create a “perfect storm” of tumorigenic potential, simultaneously promoting oncogenic transformation in epithelial cells and generating populations of bystander tumor-promoting cells while restricting immune activation.…”

Gut Microbiota and Colon Cancer: A Role for Bacterial Protein Toxins?

“…The colonization of CRC patients by CoPEC is associated with a decrease of tumor-infiltrating T lymphocytes (CD3+ T-cells). Similarly, in mice, CoPEC chronic infection decreases CD3+ and CD8+ T-cells and increases colonic inflammation, suggesting that pks+ E. coli could promote a pro-carcinogenic immune environment through impairment of antitumor T-cell response [ 74 ]. Moreover, colitis-susceptible IL-10-deficient mice showed increased formation of invasive carcinoma when colonized with CoPEC, whereas deletion of the pks genotoxic island from these E. coli strains decreased tumor multiplicity and invasion [ 72 , 75 ].…”