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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 1 (01 04 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 32990678 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Histocompatibility Antigens Class I
• MAL2 protein, human
• Myelin and Lymphocyte-Associated Proteolipid Proteins
• Neoplasm Proteins

Topics

• Animals
• Antigen Presentation
• Antigens, Neoplasm (immunology)
• Breast Neoplasms (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Female
• Histocompatibility Antigens Class I (immunology)
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Myelin and Lymphocyte-Associated Proteolipid Proteins (immunology)
• Neoplasm Proteins (immunology)
• Tumor Escape