ST2 as checkpoint target for colorectal cancer immunotherapy.

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.

• Authors: Kevin Van der Jeught, Yifan Sun, Yuanzhang Fang, Zhuolong Zhou, Hua Jiang, Tao Yu, Jinfeng Yang, Malgorzata M Kamocka, Ka Man So, Yujing Li, Haniyeh Eyvani, George E Sandusky, Michael Frieden, Harald Braun, Rudi Beyaert, Xiaoming He, Xinna Zhang, Chi Zhang, Sophie Paczesny, Xiongbin Lu
• Journal: JCI insight (JCI Insight) Vol. 5 Issue 9 (05 07 2020) ISSN: 2379-3708 [Electronic] United States
• PMID: 32376804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• IL1RL1 protein, human
• Il1rl1 protein, mouse
• Il33 protein, mouse
• Interleukin-1 Receptor-Like 1 Protein
• Interleukin-33

Topics

• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (immunology)
• Databases, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-1 Receptor-Like 1 Protein (immunology)
• Interleukin-33 (immunology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Tumor Microenvironment (immunology)
• Tumor-Associated Macrophages (cytology, immunology)