2. Academic Validation
  3. A membrane-associated MHC-I inhibitory axis for cancer immune evasion

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

  • Cell. 2023 Aug 8;S0092-8674(23)00783-3. doi: 10.1016/j.cell.2023.07.016.
Xufeng Chen 1,  Qiao Lu 1,  Hua Zhou 2,  Jia Liu 1,  Bettina Nadorp 1,  Audrey Lasry 1,  Zhengxi Sun 1,  Baoling Lai 3,  Gergely Rona 4,  Jiangyan Zhang 1,  Michael Cammer 5,  Kun Wang 1,  Wafa Al-Santli 1,  Zoe Ciantra 6,  Qianjin Guo 7,  Jia You 1,  Debrup Sengupta 8,  Ahmad Boukhris 1,  Hongbing Zhang 9,  Cheng Liu 9,  Peter Cresswell 8,  Patricia L M Dahia 7,  Michele Pagano 4,  Iannis Aifantis 10,  Jun Wang 11
Affiliations

Affiliations

  • 1 Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
  • 2 Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 3 Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 4 The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 5 Microscopy Core, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 6 Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 7 Department of Medicine, Division of Hematology and Medical Oncology, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 8 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
  • 9 Eureka Therapeutics Inc., Emeryville, CA 94608, USA.
  • 10 Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA. Electronic address: [email protected].
  • 11 Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA. Electronic address: [email protected].
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.

Keywords

MHC-I; SUSD6; T cell; TMEM127; WWP2; antigen presentation; cancer; immune evasion; lysosomal degradation; ubiquitination.

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