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

肿瘤微环境 癌症研究 结直肠癌 生物 转录组 细胞毒性T细胞 癌症 免疫系统 免疫学 遗传学 体外 基因表达 基因
作者
Nilmara de Oliveira Alves,Olivier Boulard,Amaury Vaysse,Guillaume Dalmasso,Darja Nikitina,Richard Ruez,Thierry Pédron,Emma Bergstein,Pierre Sauvanet,Diane Letourneur,Catherine Godfraind,Imène Najjar,Emmanuel Lemichez,Juan Iovanna,Denis Mestivier,Nicolas Barnich,Philippe Sansonetti,Christophe Malabat,Marc Monot,Sean Kennedy,Amel Mettouchi,Richard Bonnet,Iradj Sobhani,Mathias Chamaillard
标识
DOI:10.1101/2023.03.13.523827
摘要

ABSTRACT Intratumoral bacteria locally contribute to cellular and molecular tumor heterogeneity that support cancer stemness through poorly understood mechanisms. This study aims to explore how Colibactin-producing Escherichia coli (CoPEC) flexibly alters the tumor microenvironment in right-sided colorectal cancer (CRC). Metabolomic and transcriptomic spatial profiling uncovered that CoPEC colonization establishes a high-glycerophospholipid microenvironment within the tumor that is conducive to exhaustion of infiltrated CD8 + T cell and has a lowered prognostic value in right-sided CRC. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress and supply with sufficient energy for sustaining cell survival and lowering tumor immunogenicity. Specifically, a heightened phosphatidylcholine remodeling of CoPEC-infected cancer cells by the enzyme of the Land’s cycle coincided with a lowered accumulation of proapoptotic ceramide and lysophosphatidylcholine. Consequently, a reduced infiltration of CD8 + T lymphocytes that produce the cytotoxic cytokines IFN-γ was found where invading bacteria have been geolocated. By contrast, such an immunosuppressive dysmetabolic process was not observed when human colon cancer cells were infected with the mutant strain that did not produce colibactin (11G5δClbQ). This work revealed an unexpected property of CoPEC on lipid overload within tumors that could locally provide an inflammatory environment leading to immunosuppressive mechanisms and tumor expansion. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

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