Browsing by Author "Beyaert, Rudi"

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    ST2 as checkpoint target for colorectal cancer immunotherapy
    (American Society for Clinical Investigation, 2020-05-07) Jeught, Kevin Van der; Sun, Yifan; Fang, Yuanzhang; Zhou, Zhuolong; Jiang, Hua; Yu, Tao; Yang, Jinfeng; Kamocka, Malgorzata M.; So, Ka Man; Li, Yujing; Eyvani, Haniyeh; Sandusky, George E.; Frieden, Michael; Braun, Harald; Beyaert, Rudi; He, Xiaoming; Zhang, Xinna; Zhang, Chi; Paczesny, Sophie; Lu, Xiongbin; Pediatrics, School of Medicine
    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.