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.