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Bulk RNA-Seq analysis of adoptively co-transferred PKM2 wildtype and PKM2 knockout CD8+ T cells into tumor-bearing mice subsequently treated with and without PD-1 checkpoint blockade

ABSTRACT: In this study we investigated how manipulation of the glycolytic enzyme pyruvate kinase muscle 2 (PKM2) alters CD8+ T cell gene expression and responsiveness to PD-1 checkpoint blockade in orthotopic mouse lung adenocarcinoma. In this dataset, we performed adoptive co-transfers of antigen-specific OT-I+ Thy1.1+ CD8+ T cells genetically modified by CRISPR/Cas9 ribonucleoproteins to become PKM2 knockout (in Thy1.1+/- cells) or PKM2 wildtype (in Thy1.1+/+ cells). T cells were transferred into orthotopic mouse lung adenocarcinoma HKP1-ova-GFP tumor-bearing syngeneic C57BL/6 mice, and subsequently mice were treated with either IgG or anti-PD-1. Adoptively-transferred T cells were sorted based on Thy1.1 zygosity from tumors at two different time points and bulk RNA sequenced.

ORGANISM(S): Mus musculus

PROVIDER: GSE216675 | GEO | 2023/10/19

REPOSITORIES: GEO

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Project description:Purpose: PKM2-mediated metabolic switch to aerobic glycolysis plays a critical role in promoting cell survival and proliferation. However, little is known about the function of intestinal epithelial PKM2 in intestinal homeostasis. Here we investigated whether and how intestinal epithelial PKM2 modulates the morphology and function of the adult intestine in experimental murine colitis. Methods: Colonoscopic biopsies from the Crohn’s disease (CD) and ulcerative colitis (UC) patients (10 each) were analyzed for PKM2 expression. We also generated intestinal epithelial-specific Pkm2 knockout mice and employed them to examine PKM2 function. Mouse intestinal inflammation was induced with dextran sulfate sodium (DSS) in drinking water. Disease phenotypes were investigated by mouse survival, body weight, colon length and analysis of immune cell infiltration in colon, intestinal epithelial cell gene profiling and signal pathway. Results: Intestinal epithelial PKM2 level in UC and CD patients was significantly decreased compared to that from non-inflamed intestinal epithelium. Similar reduction of intestinal epithelial PKM2 was observed in mice with experimental colitis. Supporting the notion that PKM2 serves as a safeguard against colitis, intestinal epithelial-specific Pkm2-deficient (Pkm2-/-) mice displayed a severer intestinal inflammation, companying with shortened colon, disruption of epithelial tight junction, higher permeability, elevation of inflammatory cytokines and immune cell infiltration, compared with wild-type mice. Gene profiling and western blot analysis indicated that cell survival signaling, particularly the Akt/β-catenin pathways, were downregulated in Pkm2-/- mice. Functional assay using mouse primary colonic epithelial cells confirmed that Pkm2 reduction decreased proliferation and migration of epithelial cells, while enhanced expression of Pkm2 was associated with increased transcriptional activity of β-catenin. Moreover, increasing mouse intestinal epithelial Pkm2 expression via delivery of Pkm2-expressing plasmid attenuated DSS-induced experimental colitis. Conclusions: Intestinal epithelial PKM2, through activating Wnt/β-catenin signaling, induces a strong proliferative and migratory response that increases cell survival and wound healing under colitic condition.

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Bulk RNA-Seq analysis of adoptively co-transferred PKM2 wildtype and PKM2 knockout CD8+ T cells into tumor-bearing mice subsequently treated with and without PD-1 checkpoint blockade

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