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.
View: Text | PDF
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

×

Figure 3

MAL2 expression is correlated with low cytotoxicity of tumor-infiltrating CD8+ T cells.

Options: View larger image (or click on image) Download as PowerPoint
MAL2 expression is correlated with low cytotoxicity of tumor-infiltratin...
(A) Violin plots representing relative cytotoxicity (RC) level of tumor-infiltrating CD8+ T cells and normalized expression levels of 3 cytotoxicity markers in TNBC samples with high or low MAL2 expression levels. The data of TNBC patients are from TCGA cohort. Unpaired 2-tailed t test was used for statistical analysis. (B) Expression of MAL2 was quantified by log(TPM+1) in immune cells, stromal cells, and TNBC tumor cells in the GSE75688 scRNA-Seq data set. One-way ANOVA test was used for statistical analysis. (C) MAL2 expression is negatively associated with the expression levels of TCR signaling genes in TNBC patient samples. The heatmap shows the expression levels of the TCR signaling genes in the samples. Each row is 1 TCR signaling gene and each column is 1 sample. The genes are ordered by their coexpression correlation with MAL2 (low to high from top to bottom). The histogram on the right illustrates the distribution of the coexpression correlation between MAL2 and the TCR signaling genes. x-axis, correlation values; y-axis: TCR gene counts. (D) CD8+ T cells isolated from EO771-derived tumors with different levels of Mal2 (WT, OE, and KD) in C57BL/6 mice were analyzed by flow cytometry for their activity indicated by IFN-γ, TNF-α, and GZMB levels in the cell. Flow cytometrical data are shown on the left, and the quantitative results are summarized on the right. ***P < 0.001, 1-way ANOVA test. Data are presented as mean ± SD and are representative of 3 independent experiments. (E) CD8+ T cells as above mentioned were analyzed for their secretion of cytokines (IFN-γ, TNF-α). Supernatants were collected and quantified by ELISA. ***P < 0.001, 2-way ANOVA test. Data are presented as mean ± SD and are representative of 3 independent experiments.