Abstract 152P
Background
Interleukin-38 (IL-38) is a newly discovered cytokine of IL-1 family which suppresses T cell activation and facilitates the resolution of inflammation. Despite this, its role in carcinogenesis remains poorly understood.
Methods
Human colon adenocarcinoma tissue microarrays were stained with IL-38, CD8, γδTCR, CD4, CD20 and CD3 via multiplexed immunofluorescence. IL-38 knockout (Il1f10-/-) and epithelium-specific IL-38 knockout (Il1f10△Villin) mice, alongside control groups were subjected to azoxymethane/dextran sodium sulfate (AOM/DSS) challenge. Antibodies against IL-38 were applied to wild-type mice with AOM/DSS treatment at the colitis or tumor stage. Flow cytometry and multiplexed immunofluorescence were conducted to delineate immune profiles and tertiary lymphoid structure (TLS) formation in intestinal tissues.
Results
In tissues from human colon adenocarcinoma, elevated IL-38 expression was observed compared with healthy controls, correlating negatively with infiltration of T cells and mismatch repair gene mutations. High epithelial IL-38 levels inversely correlated with the overall survival of patients with microsatellite stable tumors. Il1f10-/- mice and mice treated with an antibody neutralizing IL-38 exhibited exacerbated colitis but, surprisingly, fewer tumors in AOM/DSS model. Elevated inflammatory cytokine levels were noted, which correlated with heightened T cell infiltration and abundant TLS formation. Il1f10△Villin mice exhibited reduced tumor burden without developing severe colitis akin to Il1f10-/- mice and mice treated with anti-IL-38 antibodies.
Conclusions
Our findings revealed significantly elevated IL-38 levels in intestinal tissues from colon cancer patients compared to healthy individuals, exhibiting a negative correlation with patient outcomes. Inhibition of IL-38, either genetically or by an antibody-mediated blockade, facilitates T cell recruitment and TLS assembly, and consequently impeding colon carcinogenesis. Thus, agents targeting IL-38 represent a promising avenue for the prevention and treatment of colorectal cancer, particularly for patients with microsatellite stable tumors that do not benefit from current immunotherapy strategies.
Legal entity responsible for the study
The authors.
Funding
The abstract was supported by Deutsche Krebshilfe (70114051), Deutsche Forschungsgemeinschaft (SFB 1039, TP B06; GRK 2336, TP1), and the LOEWE Center Frankfurt Cancer Institute (FCI), funded by the Hessen State Ministry for Higher Education, Research and the Arts.
Disclosure
All authors have declared no conflicts of interest.