TY - JOUR AU - Van der Jeught, Kevin AU - Sun, Yifan AU - Fang, Yuanzhang AU - Zhou, Zhuolong AU - Jiang, Hua AU - Yu, Tao AU - Yang, Jinfeng AU - Kamocka, Malgorzata M. AU - So, Ka Man AU - Li, Yujing AU - Eyvani, Haniyeh AU - Sandusky, George E. AU - Frieden, Michael AU - Braun, Harald AU - Beyaert, Rudi AU - He, Xiaoming AU - Zhang, Xinna AU - Zhang, Chi AU - Paczesny, Sophie AU - Lu, Xiongbin T1 - ST2 as checkpoint target for colorectal cancer immunotherapy PY - 2020/05/18/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.136073 VL - 5 IS - 9 UR - https://doi.org/10.1172/jci.insight.136073 PB - The American Society for Clinical Investigation ER -