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ST2 as checkpoint target for colorectal cancer immunotherapy
Kevin Van der Jeught1, Yifan Sun1, Yuanzhang Fang1
1Department of Medical and Molecular Genetics.
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.
Insights
High ST2 expression in colorectal cancer (CRC) correlates with poor survival and immunosuppression. Targeting ST2, particularly on tumor-associated macrophages, alongside immunotherapy, shows promise for improving CRC treatment outcomes.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Immune checkpoint blockade immunotherapy shows promise in colorectal cancer (CRC), but durable responses are limited.
- The tumor microenvironment (TME) significantly influences anti-tumor immunity and patient outcomes in CRC.
- Identifying novel TME-associated checkpoint targets is crucial for enhancing CRC immunotherapy efficacy.
Purpose of the Study:
- To investigate the role of Interleukin-33 receptor (ST2) in the CRC TME.
- To evaluate ST2 as a potential therapeutic target for improving colorectal cancer immunotherapy.
Main Methods:
- Analysis of ST2 expression in CRC patient samples and correlation with survival and CD8+ T cell cytotoxicity.
- Preclinical studies in CRC models using ST2 knockout (ST2-KO) mice and combination therapy with anti-PD-1.
- Assessment of IL-33trap fusion protein efficacy in suppressing CRC tumor growth.
Main Results:
- High ST2 expression in CRC patients is linked to poor survival and reduced CD8+ T cell activity.
- ST2 is predominantly expressed on tumor-associated macrophages (TAMs) in CRC.
- ST2+ TAMs are recruited via CXCR3, promote an immunosuppressive TME, and their depletion combined with anti-PD-1 therapy inhibits CRC growth.
- IL-33trap treatment suppressed CRC tumor growth and reduced ST2+ TAMs.
Conclusions:
- ST2 is a key factor in the immunosuppressive CRC TME, associated with poor prognosis.
- Targeting ST2, especially on TAMs, represents a promising strategy to enhance colorectal cancer immunotherapy.
- ST2 inhibition, through genetic depletion or IL-33trap, effectively reduces tumor growth in preclinical CRC models.
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