免疫检查点阻断已经彻底改变了癌症治疗，但是一些癌症，如急性髓细胞白血病（AML），并不对其产生反应或者产生耐药性。一种潜在的耐药模式是通过异常的主要组织相容性复合物I类（MHC-I）抗原呈递（AP）来逃避T细胞免疫反应。为了绘制这样的耐药机制，我们在AML中利用特定的肽-MHC-I引导的CRISPR-Cas9筛选来鉴定关键的MHC-I调控因子。排名靠前的负调控因子有表面蛋白寿司结构域含6（SUSD6），跨膜蛋白127（TMEM127）和E3泛素连接酶WWP2。SUSD6在AML和多种实体癌中高度表达，其消除增强了MHC-I抗原呈递并减少了依赖CD8+ T细胞的肿瘤生长。在机制上，SUSD6与TMEM127和MHC-I形成三聚体复合物，进而招募WWP2进行MHC-I泛素化和溶酶体降解。结合SUSD6/TMEM127/WWP2基因特征，其与癌症生存率呈负相关，我们的发现定义了一个与细胞膜相关的MHC-I抑制轴作为潜在的治疗靶点，适用于白血病和实体癌。版权所有©2023 Elsevier Inc. 保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.