| First Author | Chen X | Year | 2023 |
| Journal | Cell | Volume | 186 |
| Issue | 18 | Pages | 3903-3920.e21 |
| PubMed ID | 37557169 | Mgi Jnum | J:340610 |
| Mgi Id | MGI:7528546 | Doi | 10.1016/j.cell.2023.07.016 |
| Citation | Chen X, et al. (2023) A membrane-associated MHC-I inhibitory axis for cancer immune evasion. Cell 186(18):3903-3920.e21 |
| abstractText | 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. |
