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TMED10 inhibition suppresses cell-surface PD-1 expression and overcomes T cell dysfunction

ABSTRACT: TMED10 inhibition suppresses cell-surface PD-1 expression and overcomes T cell dysfunction

PROVIDER: PRJNA1063308 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27483452_1.fastq.gz	Fastqsanger.gz
	SRR27483452_2.fastq.gz	Fastqsanger.gz
	SRR27483453_1.fastq.gz	Fastqsanger.gz
	SRR27483453_2.fastq.gz	Fastqsanger.gz
	SRR27483454_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

TMED10 inhibition suppresses cell-surface PD-1 expression and overcomes T cell dysfunction

Project 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

2024-12-05 | GSE252956 | GEO

TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction.

Project description: Not available

| S-EPMC11552591 | biostudies-literature

TMED10 INHIBITION SUPPRESSES CELL-SURFACE PD-1 EXPRESSION AND REVERSES T CELL DYSFUNCTION

2025-05-06 | PXD026984 | Pride

Nuclear compartmentalization of PD-L1 suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance via histone macroH2A1 phosphorylation

Project description:Nuclear compartmentalization of PD-L1 suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance via histone macroH2A1 phosphorylation

| PRJNA1157219 | ENA

Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance

Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.

2022-03-31 | MSV000089180 | MassIVE

TMED10 regulates cell-surface expression of PD-1

Project description:We found that Tmed10 regulates the cell-surface expression of PD-1 in T cells. We additionally show that treatment with AGN192403 can phenocopy Tmed10 KO by lysosomally degrading the Tmed10-PD-1 complex.

2023-11-10 | GSE161211 | GEO

Nuclear compartmentalization of PD-L1 suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance via histone macroH2A1 phosphorylation

Project description:Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more significantly in immunocompetent mice. p-AMPKα facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK-STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which may result from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to IFN-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

2024-11-20 | GSE276400 | GEO

PD-1-PD-L1 Axis Activation Suppresses CD8+ T Cells and Improves Nephritis.

Project description:PD-1-PD-L1 Axis Activation Suppresses CD8+ T Cells and Improves Nephritis.

| PRJNA951663 | ENA

TMED10 regulates cell-surface expression of PD-1

Project description:TMED10 regulates cell-surface expression of PD-1

| PRJNA675877 | ENA

Memory B cell subset defined by CD80 and PD-L2 surface expression

Project description:NP-reactive murine splenic memory B cells were sorted based on the expression of the surface markers CD80 and PD-L2 AM14 tg+ X Vk8R+/- recipients of B1-8+ B cells were immunized with NP-CGG and 8 weeks later splenic EMA-, CD19+ and NP+ memory B cells were sorted based on their surface expression of CD80 and PD-L2 (DN=CD80- PDL2-, SP=CD80- PDL2+, DP=CD80+ PDL2+). 1x10E5 up to 3x10E5 cells per sample were sorted and total RNA was isolated using the RNeasy plus micro kit and cRNA was prepared using the Illumina TotalPrep RNA Amplification Kit.

2014-05-06 | E-GEOD-51604 | biostudies-arrayexpress

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