A Membrane-associated MHC-I Inhibitory Axis for Cancer Immune Evasion

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Aug 9

PMID 37557169

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

Affiliations

Soon will be listed here.

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.

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