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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2021 May 17; Vol. 131 (10). - Publication Year :
- 2021
-
Abstract
- One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.
- Subjects :
- Animals
Antigens, Neoplasm genetics
HCT116 Cells
Humans
Immune Checkpoint Inhibitors pharmacokinetics
Immunity, Cellular genetics
Lactones pharmacokinetics
Mice
Mice, Inbred BALB C
Mice, Transgenic
Neoplasm Proteins genetics
Neoplasm Proteins immunology
Neoplasms, Experimental genetics
Neoplasms, Experimental immunology
RNA-Binding Proteins genetics
RNA-Binding Proteins immunology
Sesquiterpenes pharmacokinetics
Antigen Presentation drug effects
Antigens, Neoplasm immunology
CD8-Positive T-Lymphocytes immunology
Immune Checkpoint Inhibitors pharmacology
Immunity, Cellular drug effects
Immunotherapy
Lactones pharmacology
Neoplasms, Experimental therapy
Sesquiterpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 131
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 33830945
- Full Text :
- https://doi.org/10.1172/JCI146832