In patients with colorectal cancer (CRC), expression of IL-33 receptor ST2 correlated with reduced survival and CD8+ T cell cytotoxicity, and was found predominantly on tumor-associated macrophages (TAMs). Murine TAMs upregulated ST2 upon IL-33 exposure, and ST2+ TAMs displayed a suppressive phenotype and accumulated within CRC tumors. Tumor infiltration by CD8+ T cells and antigen-specific expansion following immunization increased in ST2-/- mice. CRC tumor control was observed in WT mice treated with a fusion protein sequestering IL-33 or an anti-CSF1R antibody and was enhanced with anti-PD-1 antibody in ST2-/- mice.
Contributed by Alex Najibi
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.
Author Info: (1) Department of Medical and Molecular Genetics. (2) Department of Medical and Molecular Genetics. (3) Department of Medical and Molecular Genetics. (4) Department of Medical and
Author Info: (1) Department of Medical and Molecular Genetics. (2) Department of Medical and Molecular Genetics. (3) Department of Medical and Molecular Genetics. (4) Department of Medical and Molecular Genetics. (5) Department of Pediatrics. (6) Department of Medical and Molecular Genetics. (7) Department of Pediatrics. (8) Department of Medicine, Division of Nephrology. (9) Center for Computational Biology and Bioinformatics. (10) Department of Medical and Molecular Genetics. (11) Department of Medical and Molecular Genetics. (12) Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. (13) Department of Medical and Molecular Genetics. (14) VIB Center for Inflammation Research, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (15) VIB Center for Inflammation Research, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (16) Fischell Department of Bioengineering and. Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland, USA. (17) Department of Medical and Molecular Genetics. Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. (18) Department of Medical and Molecular Genetics. Center for Computational Biology and Bioinformatics. Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. (19) Department of Pediatrics. Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. (20) Department of Medical and Molecular Genetics. Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
