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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."],"repository":["ENA"],"description_synonyms":["dysfunction., dTAF[[II]]230, TAF[[II]]250, d230, 1110014C03Rik, Thymus-Dependent Lymphocytes, external covering of organism, SLEB2, TAF200, l17, l(3)84Ab, dTAFII250, organism surface, BG:DS00004.13, T-Lymphocyte, TAFII-250, TAF250/230, EfW1, Cell, dTAF230, dmTAF[[II]]230, Tmp21, surface, TAFII250, RPL23, rpl17a, T Lymphocyte, dmTAF1, T-Cell, Taf230, p230, pd-1, p23, TAF[[II]]250/230, TFIID, TMP21, immature T cell, T lymphocyte, S31I125, PD1, p24delta1, PD-1, integumentum commune, TAF250, Taf[[II]]250, Ly101, Taf200, T-cell, dTAF[[II]]250, TAF[[II]]230, S31III125, TFIID TAF250, Tmp-21-I, cel, cell, body surface, T-Cells, Thymus-Dependent, 60S ribosomal protein L23, T, Taf1p, rpl23, Lymphocytes, TAF[II]250, pathophysiology, T-lymphocyte, CG17603, TAF[[II]], CD279, hPD-1, Thymus-Dependent Lymphocyte, dTAF250, T Cells, hPD-l, P24(DELTA), DmelCG17603, T cell, Pdc1, Taf250, integumentary system, SR3-5, hSLE1, mature T cell, rpl17, Cells, L17, T Cell, TAF, dermal system, T Lymphocytes, Thymus Dependent Lymphocytes, TAF230, Lymphocyte, TAF1"],"name_synonyms":["dysfunction., dTAF[[II]]230, TAF[[II]]250, d230, 1110014C03Rik, Thymus-Dependent Lymphocytes, external covering of organism, SLEB2, TAF200, l17, l(3)84Ab, dTAFII250, organism surface, BG:DS00004.13, T-Lymphocyte, TAFII-250, TAF250/230, EfW1, Cell, dTAF230, dmTAF[[II]]230, Tmp21, surface, TAFII250, RPL23, rpl17a, T Lymphocyte, dmTAF1, T-Cell, Taf230, p230, pd-1, p23, TAF[[II]]250/230, TFIID, TMP21, immature T cell, T lymphocyte, S31I125, PD1, p24delta1, PD-1, integumentum commune, TAF250, Taf[[II]]250, Ly101, Taf200, T-cell, dTAF[[II]]250, TAF[[II]]230, S31III125, TFIID TAF250, Tmp-21-I, cel, cell, body surface, T-Cells, Thymus-Dependent, 60S ribosomal protein L23, T, Taf1p, rpl23, Lymphocytes, TAF[II]250, pathophysiology, T-lymphocyte, CG17603, TAF[[II]], CD279, hPD-1, Thymus-Dependent Lymphocyte, dTAF250, T Cells, hPD-l, P24(DELTA), DmelCG17603, T cell, Pdc1, Taf250, integumentary system, SR3-5, hSLE1, mature T cell, rpl17, Cells, L17, T Cell, TAF, dermal system, T Lymphocytes, Thymus Dependent Lymphocytes, TAF230, Lymphocyte, TAF1"],"additional_accession":[]},"is_claimable":false,"name":"TMED10 inhibition suppresses cell-surface PD-1 expression and overcomes T cell dysfunction","description":"TMED10 inhibition suppresses cell-surface PD-1 expression and overcomes T cell dysfunction","dates":{"last_updated":"2025-09-24","first_public":"2024-12-08"},"accession":"PRJNA1063308","cross_references":{"GEO":["GSE252956"],"taxon":["10090"],"PubMed":["39510795"]}}