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
  • 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.
Products