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Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk promoting immunosuppression and immunotherapy resistance

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE196790 | GEO | 2024/03/28

REPOSITORIES: GEO

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Project description:The project aims to identify metabolic genes and pathways associated with immunotherapy resistance. Methods: 4x10e6 Panc02, 1x10e6 MC38 or 2x10e6 CT26 cells were injected subcutaneously (s.c.) in the right flank of the mouse in a final suspension of 200μl PBS. Tumor volumes were measured at least three times per week. At the indicated time points, mice were randomized and treated intraperitoneally (i.p.) with 10 mg/kg α-PD-1 (BioXcell) or α-CTLA4 or control IgG from rat serum (Sigma-Aldrich). At end-stage, tumor-bearing mice were sacrificed by cervical dislocation and RNA was isolated from tumor tissue using TRIzol (Life Technologies). Starting from total RNA, poly-adenylated fragments were isolated, reverse transcribed and converted into indexed sequencing libraries using the Illumina TruSeq RNA sample preparation kit V2 according to the manufacturer’s instructions. The first 50 bases of these libraries were sequenced on a HiSeq 2500 system (Illumina, San Diego, CA). Raw sequencing reads were mapped to the transcriptome and the mouse reference genome (GRCm38/mm10) using TopHat 2.0 and Bowtie2.0 (Langmead and Salzberg, 2012). Mapped reads were assigned to ensemble gene IDs with the HTSeq software package. Transcriptome profiling was performed in three different murine cancer models (MC38, CT26 and panc02) treated with PD-1, CTLA-4 or vehicle Our bulk tumor transcriptomic profiles of responsive (MC38), low responsive (CT26) and non-responsive (PancO2) murine tumor models were integrated with publicly available pretreatment transcriptomic datasets of patients responding and resistant to immune checkpoint inhibitors, such as α-CTLA-4 and α-PD-1 (Van Allen- et al., Science 2015; Hugo et al., Cell 2016; Ascierto et al., Cancer Imm Research 2016). All these datasets were interpreted by using our in-house BIOMEX platform (Goveia et al., EMBO Mol Med 2016), which focuses on metabolic profiles. Metabolic genes were ranked, prioritizing the most consistently upregulated genes associated with resistance to immuno checkpoint inhibitors (ICIs).

Project description:Intestinal chronic inflammation is associated with microbial dysbiosis and accumulation of various immune cells including myeloid-derived suppressor cells (MDSC), which profoundly impact the immune microenvironment, perturb homeostasis and increase the risk to develop colitis-associated colorectal cancer (CAC). However, the specific MDSCs-dysbiotic microbiota interactions and their collective impact on CAC development remain poorly understood. In this study, using a murine model of CAC, we demonstrate that CAC-bearing mice exhibit significantly elevated levels of highly immunosuppressive MDSCs, accompanied by microbiota alterations. Both MDSCs and bacteria that infiltrate the colon tissue and developing tumors can be found in close proximity, suggesting intricate MDSC-microbiota cross-talk within the tumor microenvironment. To investigate this phenomenon, we employed antibiotic treatment to disrupt MDSC-microbiota interactions. This intervention yielded a remarkable reduction in intestinal inflammation, decreased MDSC levels, and alleviated immunosuppression, all of which were associated with a significant reduction in tumor burden. Furthermore, we underscore the causative role of dysbiotic microbiota in the predisposition toward tumor development, highlighting their potential as biomarkers for predicting tumor load. We shed light on the intimate MDSCs-microbiota cross-talk, revealing how bacteria enhance MDSC suppressive features and activities, inhibit their differentiation into mature beneficial myeloid cells, and redirect some toward M2 macrophage phenotype. Collectively, this study uncovers the role of MDSC-bacteria cross-talk in impairing immune responses and promoting tumor growth, providing new insights into potential therapeutic strategies for CAC.SignificanceMDSCs-dysbiotic bacteria interactions in the intestine play a crucial role in intensifying immunosuppression within the CAC microenvironment, ultimately facilitating tumor growth, highlighting potential therapeutic targets for improving the treatment outcomes of CAC.

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Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk promoting immunosuppression and immunotherapy resistance

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