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    ST2 as checkpoint target for colorectal cancer immunotherapy

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    Author
    Van der Jeught, K.
    Sun, Y.
    He, X.
    Date
    2020
    Journal
    JCI insight
    Publisher
    The American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/jci.insight.136073
    Abstract
    Immune checkpoint blockade immunotherapy delivers promising clinical results in colorectal cancer (CRC). However, only a fraction of cancer patients develop durable responses. The tumor microenvironment (TME) negatively impacts tumor immunity and subsequently clinical outcomes. Therefore, there is a need to identify other checkpoint targets associated with the TME. Early-onset factors secreted by stromal cells as well as tumor cells often help recruit immune cells to the TME, among which are alarmins such as IL-33. The only known receptor for IL-33 is stimulation 2 (ST2). Here we demonstrated that high ST2 expression is associated with poor survival and is correlated with low CD8+ T cell cytotoxicity in CRC patients. ST2 is particularly expressed in tumor-associated macrophages (TAMs). In preclinical models of CRC, we demonstrated that ST2-expressing TAMs (ST2+ TAMs) were recruited into the tumor via CXCR3 expression and exacerbated the immunosuppressive TME; and that combination of ST2 depletion using ST2-KO mice with anti-programmed death 1 treatment resulted in profound growth inhibition of CRC. Finally, using the IL-33trap fusion protein, we suppressed CRC tumor growth and decreased tumor-infiltrating ST2+ TAMs. Together, our findings suggest that ST2 could serve as a potential checkpoint target for CRC immunotherapy.
    Keyword
    Cancer immunotherapy
    Colorectal cancer
    Immunology
    Inflammation
    Macrophages
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85084382676&doi=10.1172%2fjci.insight.136073&partnerID=40&md5=8bcd537fb1e05f8ca72c0a9350fe8caa; http://hdl.handle.net/10713/12818
    ae974a485f413a2113503eed53cd6c53
    10.1172/jci.insight.136073
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