ST2 as checkpoint target for colorectal cancer immunotherapy
- 7 May 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
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.Funding Information
- NIH (U01CA232491)
- NIH (R01CA203737)
- IUSM (IUSM Strategic Research Initiative fund)
- NIH (P30CA082709,U54 DK106846,1S10D012270)
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