A membrane-associated MHC-I inhibitory axis for cancer immune evasion

From the lab of Gabrielle’s Angels grantee Iannis Aifantis – their latest work on peptide:MHC class I expression & degradation and the discovery of a novel protein complex potentially important for T cell recognition in cancer.

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, researchers 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, researchers’ findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers. Read more here: https://www.cell.com/cell/fulltext/S0092-8674(23)00783-3