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 Article has an altmetric score of 75

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 9

Depletion of MAL2 enhances CD8+ T cell cytotoxicity in human TNBC tumors.

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Depletion of MAL2 enhances CD8+ T cell cytotoxicity in human TNBC tumors...
(A) MAL2 levels in tumor cells affect the cytotoxicity of the tumor-infiltrating CD8+ T cells in human TNBC tumors. Tumor cells isolated from fresh TNBC tumor tissues (patient #1 and #2) were transduced with lentiviral MAL2 or its shRNA. The tumor cells formed spheroids with CAFs isolated from the same tumor tissue. The tumor spheroids were cocultured with preactivated CD8+ T cell isolated from the same tumor tissue to detect the T cell cytotoxicity (spheroid dissociation rates). Representative images of spheroids are shown. Scale bar: 100 μm. (B) Quantitative data are presented as mean ± SD of represented images from 3 parallel experiments in A. (C) Spheroids from A were digested into single cells, which were stained for EpCAM (tumor cells), anti-CD140a (CAFs), and LIVE/DEAD dead-cell stain. Flow cytometry data show the CD8+ T cell cytotoxicity in patient-derived CAF-tumor spheroids with different MAL2 expression levels. (D) The CD8+T cells collected from A were analyzed for their activity. The CD8+ T cells were incubated with 50 ng/mL PMA, 1 μg/mL ionomycin, and 5 μg/mL brefeldin A for 5 hours, and were stained with antibodies against IFN-γ, TNF-α, and GZMB. Quantitative data are presented as mean ± SD of 3 technical experiments. (E) Correlation of MAL2 levels (pathological scores) with tumor-infiltrating CD8+ T cell cytotoxicity (determined by GZMB levels) in human breast tumor tissue microarrays. Immunohistochemical analyses of MAL2, CD8, and GZMB in human TNBC TMA slides were conducted, and quantitative results were obtained as described in Supplemental Methods. Statistical analyses were conducted using 1-way ANOVA test. *P < 0.05; **P < 0.01; ***P < 0.001.