ST2 as checkpoint target for colorectal cancer immunotherapy
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
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
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Research Article Immunology Inflammation

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

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Figure 5

Inhibition of the IL-33/ST2 pathway on antigen-specific T cell responses.

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Inhibition of the IL-33/ST2 pathway on antigen-specific T cell responses...
(A–C) Injection of splenic CD8-enriched OT-I T cells into WT or ST2–/– mice (day 0). Mice were vaccinated intraperitoneally with 100 μg SIINFEKL peptide plus 100 μg poly(I:C). (A) The number of dextramer-positive (DEX) CD8+ T cells was determined from splenocytes on day 5 (representative of 2 independent experiments; n = 4 mice/group; data displayed as mean + SEM). (B) Percentages of IFN-γ– and TNF-α– expressing cells were determined upon SIINFEKL peptide restimulation (WT, n = 8; ST2–/–, n = 5; data displayed as mean + SEM). (C) Expression of PD-1 in vaccinated mice is shown (WT, n = 8; ST2–/–, n = 4; data displayed as mean + SEM). (D) Therapeutic efficacy of anti–PD-1 treatment in WT and ST2–/– mice in the subcutaneous MC38 CRC model (WT isotype, n = 9; ST2–/–, n = 7; WT anti–PD-1, n = 11; ST2–/– anti–PD-1, n = 10; data displayed as mean + SEM). (E) MACS F4/80-sorted macrophages from WT mice bearing MC38 tumors were seeded and treated or not with IL-33. ST2 intensity per cell was determined using confocal microscopy. Graph depicts the intensity of ST2 per cell (data displayed as mean + SD). Without IL33, n = 2793; with IL-33, n = 4217. (F) Dose-dependent increase in ST2 expression upon IL-33 stimulation (n = 5; data displayed as mean + SEM). (G) Schematic representation of the IL-33trap. (H) Therapeutic efficacy of IL-33trap treatment in WT mice harboring MC38 tumors (control [Ctrl], n = 6, IL-33trap, n = 5; data displayed as mean + SEM). (I) Analysis of ST2+ TAM infiltration from control and IL-33trap–treated tumors (n = 5; data displayed as mean + SD). *P < 0.05, **P < 0.01, ****P < 0.0001. Significance was determined by 2-tailed unpaired t test (A, C, E, and I), 1-way ANOVA (B) and 2-way ANOVA (D and H).