The Colibactin-ProducingEscherichia colialters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance

Abstract

The cellular heterogeneity within a variety of solid tumors is influenced by several type of tumor-associated bacteria through yet poorly understood mechanisms. Unbiased genomic analysis revealed that right-sided colorectal tumors with poorer prognosis are preferentially populated with species related to Escherichia coli, including strains that are producing colibactin. By applying metabolomic profiling in situ, the presence of colibactin-producing Escherichia coli (CoPEC) was identified to establish a high-glycerophospholipid microenvironment within right-sided colorectal tumors that are bearing mutations in either APC or KRAS. Using spatial approaches, we revealed that bacterial microniches are poorly infiltrated with CD8+ T cells. The aforementioned alterations in lipid metabolism negatively correlated with immunomodulatory and neurotrophic factors among which the human regenerating family member 3 alpha gene (REG3A). Accordingly, the loss of its ortholog enhances growth at the proximal colon of tumors with a microenvironment that impedes immune surveillance and shares similarities to human right-sided colorectal tumors. This work clarifies how the presence of colibactin-producing bacteria may locally establish tumor heterogeneity for lipid metabolism to promote cancer progression and provide unique insights both for therapeutic intervention and enabling basic research into the mechanisms of microbiota-host interaction.