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{
  "pmid": "37557169",
  "doi": "10.1016/j.cell.2023.07.016",
  "abstract": "Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers.",
  "journal": "Cell",
  "year": 2023,
  "authors": "Chen X, Lu Q, Zhou H, Liu J, Nadorp B, Lasry A, Sun Z, Lai B, Rona G, Zhang J, Cammer M, Wang K, Al-Santli W, Ciantra Z, Guo Q, You J, Sengupta D, Boukhris A, Zhang H, Liu C, Cresswell P, Dahia PLM, Pagano M, Aifantis I, Wang J",
  "mesh_terms": "[\"Humans\", \"Antigen Presentation\", \"CD8-Positive T-Lymphocytes\", \"Histocompatibility Antigens Class I\", \"HLA Antigens\", \"Neoplasms\", \"Ubiquitin-Protein Ligases\", \"Tumor Escape\"]",
  "url": "https://pubmed.ncbi.nlm.nih.gov/37557169/",
  "external_ids": {
    "doi": "10.1016/j.cell.2023.07.016",
    "corpus_id": 260708489,
    "semantic_scholar_id": "56dd4f80e392d5f038d1939dbb5d0cf68f4bed50"
  },
  "citation_count": 163
}