Journal tile: Journal of Clinical Investigation
Manuscript title: Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation
Key Box: The study confirmed that Atractylodes lactone I (ATT-1), the main component of Atractylodes rhizome (Baizhu), a Chinese herb of invigorating qi and strengthening the spleen, can effectively promote the antigen presentation of tumor cells, thereby enhancing the response efficiency of colorectal cancer to immune checkpoint inhibitor therapy, and the combination therapy with PD-1 monoclonal antibody can exert its synergistic effect. This study enriches the scientific connotation of the theory of "strengthening the body and treating cancer" in traditional Chinese medicine, and provides an evidence for the clinical application of traditional Chinese medicine combined with tumor immunotherapy.
With the clinical application of immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA-4 monoclonal antibodies, new methods have been provided for the treatment of malignant tumors, and tumor treatment has gradually entered the era of immunotherapy. However, in colorectal cancer, immune checkpoint inhibitors are only suitable for the treatment of MSI-H/dMMR colorectal cancer, accounting for about 5% of the patient population, and the effective rate of immune checkpoint inhibitors alone is only 40%. %. The development of more effective immune checkpoint blockade combination therapy is a key scientific issue in the field of immunotherapy.
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.
This work is published at Journal of Clinical Investigation, one of the highest influences in the field of clinical research. The evidence is very solid.
Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation. J Clin Invest. 2021 May 17;131(10):e146832. doi: 10.1172/JCI146832.