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.
Highlights
The immune system identifies and acts against tumor cells by adaptive cell reactions, which play a critical role in restricting tumor initiation and development
Consistent with unbiased large-scale genome-wide studies showing that MAL2 is not a gene essential for breast cancer cell proliferation [34,35,36,37], we found that altered MAL2 levels had no or minimal effects on the proliferation of murine or human triple-negative breast cancer (TNBC) cells
As a major immune response to eliminate tumor cells in the body, CD8+ T cell–mediated cytotoxicity is dependent on its recognition of tumor-specific antigens via T cell receptor (TCR)
Summary
The immune system identifies and acts against tumor cells by adaptive cell reactions, which play a critical role in restricting tumor initiation and development. Various forms of immunotherapy, including checkpoint blockade immunotherapies, have been shown to boost T cell–mediated immune responses that lead to marked and sustained clinical responses in only a limited number of patients and cancer types [4,5,6]. To execute cytotoxicity in cancer cells, CD8+ cytotoxic T lymphocytes (CTLs) recognize tumor antigens presented on the MHC-I of the cancer cell and trigger the cancer cell to undergo programmed cell death [10,11,12]. Increased expression of MHC-I molecules can be of therapeutic significance since it makes tumor cells more susceptible to lysis induced by CTLs [13, 14]. A primary mechanism by which tumors evade immune surveillance is to downregulate antigen processing and presentation activity, including deficient expression of the MHC-I complex
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