MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation
Yuanzhang Fang, … , Xiongbin Lu, Xinna Zhang
Yuanzhang Fang, … , Xiongbin Lu, Xinna Zhang
Published September 29, 2020
Citation Information: J Clin Invest. 2021;131(1):e140837. https://doi.org/10.1172/JCI140837.
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Research Article Immunology Oncology

MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation

Abstract

Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost CD8+ T cell–mediated cytotoxicity. However, this action is eventually dependent on the efficient recognition of tumor-specific antigens via T cell receptors. One primary mechanism by which tumor cells evade immune surveillance is to downregulate their antigen presentation. Little progress has been made toward harnessing potential therapeutic targets for enhancing antigen presentation on the tumor cell. Here, we identified MAL2 as a key player that determines the turnover of the antigen-loaded MHC-I complex and reduces the antigen presentation on tumor cells. MAL2 promotes the endocytosis of tumor antigens via direct interaction with the MHC-I complex and endosome-associated RAB proteins. In preclinical models, depletion of MAL2 in breast tumor cells profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that MAL2 is a potential therapeutic target for breast cancer immunotherapy.

Authors

Yuanzhang Fang, Lifei Wang, Changlin Wan, Yifan Sun, Kevin Van der Jeught, Zhuolong Zhou, Tianhan Dong, Ka Man So, Tao Yu, Yujing Li, Haniyeh Eyvani, Austyn B. Colter, Edward Dong, Sha Cao, Jin Wang, Bryan P. Schneider, George E. Sandusky, Yunlong Liu, Chi Zhang, Xiongbin Lu, Xinna Zhang

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Figure 4

Mal2 expression in tumor cells affects CD8+ T cell cytotoxicity.

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Mal2 expression in tumor cells affects CD8+ T cell cytotoxicity. (A) EO...
(A) EO771-OVA cells with different Mal2 expression levels (WT, OE, or KD) were cocultured with OT-I T cells, and T cell cytotoxicity was measured by LDH release assay. Two-way ANOVA test was used for statistical analysis. (B) EO771-OVA cells were cocultured with OT-I T cell with or without 50 ng/mL PMA for 5 hours. Supernatants were tested by ELISA for TNF-α and IFN-γ levels. Two-way ANOVA test was used for statistical analysis. (C) EO771 tumor organoids were cocultured with OT-I T cell for 30 hours. Spheroids with diameter greater than 100 μm were counted. Scale bar: 100 μm. One-way ANOVA test was used for statistical analysis. (D) EO771 tumor organoids from C were dissociated into single cells and stained with anti-EpCAM antibody and LIVE/DEAD cell stain. T cell cytotoxicity was assessed by percentages of dead tumor cells. Two-way ANOVA test was used for statistical analysis. (E) EO771-OVA cells were cocultured with OT-I T cells with control isotype or MHC-I–blocking antibody, and T cell cytotoxicity was measured. Two-way ANOVA test was used for statistical analysis. (F) NY-ESO-1–expressing human MDA-MB-468 cells with different MAL2 expression levels were cocultured with NY-ESO-1–specific T cells at the ratio of 1:10, and T cell cytotoxicity was measured. One-way ANOVA test was used for statistical analysis. (G) Human MDA-MB-468 cells with different MAL2 expression levels were cocultured with MAGE-A10 specific T cells at the ratio of 1:20 and T cell cytotoxicity was measured. One-way ANOVA test was used for statistical analysis. Data are presented as mean ± SD of 3 independent experiments in the figure. *P < 0.05; **P < 0.01; ***P < 0.001.