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Accession PRJNA1063308
Title TMED10 inhibition suppresses cell-surface PD-1 expression and overcomes T cell dysfunction
Relevance ModelOrganism
Data types Transcriptome or Gene expression
Sample scope Multiisolate
Organism Mus musculus [Taxonomy ID: 10090]
Description PD-1 immune checkpoint blockade (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression. In a whole-genome, dual- marker FACS-based CRISPR-Cas9 screen in primary murine CD8 T cells, we found that inactivation of the EMP24/GP25L/p24 protein family, most prominently TMED10, reduced PD-1 cell-surface stability, thereby augmenting T cell activity. Treatment with TMED inhibitor AGN192403 led to lysosomal degradation of the TMED-PD-1 complex and reduced PD-1 expression in intratumoral CD8 T cells in mice, thus reversing T cell dysfunction. Clinically corroborating these findings, single-cell RNA analyses revealed a positive correlation between TMED expression in tumor-infiltrating CD8 T cells (TIL), and both a T cell dysfunction signature and lack of ICB response. Similarly, patients receiving a TIL product with high TMED expression had a shorter overall survival. Our results uncover a novel mechanism of PD-1 regulation, and provide a possible opportunity for PD-1 small molecule inhibition Overall design: C57BL/6 Rag2-/- mice were inoculated with B16F10-OVA cells. On day 4, ACT was performed, administering CD8+ OT-I sgCtrl or sgTmed10. On day11, spleen and tumor were isolated and digested. Tumor samples were analyzed using flow cytometry and RNA sequencing. Moreover, CD8+ bead isolation was performed to enrich for intratumoral CD8+ T cell population ahead of RNA sequencing. Overall, RNAseq data was derived from T cells before inoculation, from treated tumors and ultimately, from CD8+ enriched intratumoral fractions.
Publication
PubMed ID Article title Journal name DOI Year
39510795
External link
Link description
Organization Peeper, Molecular Oncology and Immunology, Netherlands Cancer Institute
Data Source NCBI

Project Data

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Experiment (22)  show -