Jeught, Kevin Van derSun, YifanFang, YuanzhangZhou, ZhuolongJiang, HuaYu, TaoYang, JinfengKamocka, Malgorzata M.So, Ka ManLi, YujingEyvani, HaniyehSandusky, George E.Frieden, MichaelBraun, HaraldBeyaert, RudiHe, XiaomingZhang, XinnaZhang, ChiPaczesny, SophieLu, Xiongbin2020-11-092020-11-092020-05-07Jeught, K. V. der, Sun, Y., Fang, Y., Zhou, Z., Jiang, H., Yu, T., Yang, J., Kamocka, M. M., So, K. M., Li, Y., Eyvani, H., Sandusky, G. E., Frieden, M., Braun, H., Beyaert, R., He, X., Zhang, X., Zhang, C., Paczesny, S., & Lu, X. (2020). ST2 as checkpoint target for colorectal cancer immunotherapy. JCI Insight, 5(9). https://doi.org/10.1172/jci.insight.1360730021-9738https://hdl.handle.net/1805/24320Immune 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.en-USImmunologyInflammationCancer immunotherapyColorectal cancerMacrophagesArticle