A Membrane-Associated Mhc-I Inhibitory Axis for Cancer Immune Evasion

Authors

• Xufeng Chen
• Qiao Lu
• Hua Zhou
• Jia Liu
• Bettina Nadorp
• Audrey Lasry
• Zhengxi Sun
• Baoling Lai
• Gergely Rona
• Jiangyan Zhang
• Michael Cammer
• Kun Wang
• Wafa Al-Santli
• Zoe Ciantra
• Qianjin Guo
• Jia You
• Debrup Sengupta
• Ahmad Boukhris
• Hongbing Zhang
• Cheng Liu
• Peter Cresswell
• Patricia L M Dahia
• Michele Pagano
• Iannis Aifantis
• Jun Wang

Language

English

Publication Date

8-31-2023

Journal

Cell

DOI

10.1016/j.cell.2023.07.016

PMID

37557169

PMCID

PMC10961051

PubMedCentral® Posted Date

3-24-2024

PubMedCentral® Full Text Version

Author MSS

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 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 CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a tri-molecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6-TMEM127-WWP2 gene signature negatively-correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as potential therapeutic targets for both leukemia and solid cancers.

Keywords

Humans, Antigen Presentation, CD8-Positive T-Lymphocytes, Histocompatibility Antigens Class I, HLA Antigens, Neoplasms, Ubiquitin-Protein Ligases, Tumor Escape, Cancer, Immune evasion, Antigen presentation, MHC-I, T cell, SUSD6, TMEM127, WWP2, AML, Solid tumor, Ubiquitination, Lysosomal degradation, Immunotherapy

Published Open-Access

yes

Recommended Citation

Chen, Xufeng; Lu, Qiao; Zhou, Hua; et al., "A Membrane-Associated Mhc-I Inhibitory Axis for Cancer Immune Evasion" (2023). Faculty, Staff and Student Publications. 4288.
https://digitalcommons.library.tmc.edu/uthmed_docs/4288