Immune MAL2-practice: breast cancer immunoevasion via MHC class I degradation
Devin Dersh, Jonathan W. Yewdell
Devin Dersh, Jonathan W. Yewdell
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e144344. https://doi.org/10.1172/JCI144344.
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Commentary

Immune MAL2-practice: breast cancer immunoevasion via MHC class I degradation

Abstract

The success of tumor immunotherapy, while partial, confirms the existence and importance of tumor immunosurveillance. CD8+ T cell recognition of tumor-specific peptides bound to MHC class I (MHC-I) molecules is central to this process. In this issue of the JCI, Fang, Wang, et al. describe a unique tumor immunoevasion strategy based on endocytosis and degradation of MHC-I complexes mediated by the trafficking factor MAL2. Notably, MAL2 expression was associated with poor prognosis of breast cancer, and its downregulation enhanced CD8+ T cell recognition of breast cancer in various experimental models. This work demonstrates that a deeper understanding of tumor interference with MHC-I stability and trafficking has considerable potential for enhancing immunotherapies.

Authors

Devin Dersh, Jonathan W. Yewdell

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Figure 1

Model for the MHC-I antigen processing pathway and evasion strategies.

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Model for the MHC-I antigen processing pathway and evasion strategies. O...
Oligopeptides destined for MHC-I complexes are typically generated in the cytosol by proteasome-mediated degradation. Peptides are imported into the endoplasmic reticulum (ER) by TAP, the transporter associated with antigen processing. The ER lumen is the site of heterotrimer assembly, where heavy chains, β2-microglobulin, and a high-affinity peptide associate while bound to TAP with the assistance of dedicated and general purpose chaperones. Assembled MHC-I is delivered to the cell surface via the Golgi complex. Cancer cells often interfere in this process to evade CD8+ T cells, although current understanding of immunoevasion has focused on genetic, transcriptomic, and signaling alterations. Highlighted in red are putative and known pathways that can contribute to immunoevasion at the posttranslational level. Fang, Wang, et al. (7) showed that MAL2 promotes endocytosis to reduce tumor antigens on the surface of breast cancer cells. ERAD, ER-associated degradation; PTMs, posttranslation modifications; UPR, unfolded protein response.