Abstract
Targeted treatments against colorectal cancer (CRC) and inflammatory bowel disease (IBD) can significantly improve quality of life, but individual responsiveness varies. An emerging drug target in both settings is interleukin 6 (IL-6). IL-6 is expressed by macrophages (Mφ), which can differentiate to a pro-inflammatory state (M1) and contribute to IBD, or an anti-inflammatory state (M2) and promote CRC. A single nucleotide polymorphism (SNP) rs1800795 in the IL6 gene influences IL-6 expression, and is associated with both IBD (C allele) and CRC (G allele). We hypothesize that rs1800795 would affect responsiveness to IL-6 targeted drugs, making it a potential predictive marker for treatment response.
Bone marrow-derived monocytes (BMDMs) from our novel mouse model carrying the SNP (B6.IL6Tmrs1800795-CFle) were differentiated ex vivo into M1 (using LPS and IFNγ) or M2 (using IL-4) states. Differentiation mRNA markers for M1 (Cd38 and Tnf-α) and M2 (Arg1 and Erg2) were measured using RT-qPCR. Following, mice were subjected to 5 days of 2% dextran sodium sulfate (DSS) to induce colitis (n = 9 per group) and injected intraperitoneally with a drug targeting IL-6 (Olamkicept, 0.5 mg/kg) or placebo (phosphate-buffered saline). Diarrhoea and bleeding was documented, and colon immune cells were isolated to measure differentiation mRNA markers.
BMDMs from healthy mice with the GG genotype showed increased M1 marker expression (P = 0.002, one-way ANOVA with Tukey’s post-hoc analysis), while no significant difference was observed in M2 markers compared to the CC genotype. Following DSS treatment, CC genotype mice experienced more severe symptoms, elevated IL-6 expression (P = 0.03, one-way ANOVA) and greater weight loss compared to their GG siblings (-14.2±1.7% vs. -6.3±1.9%, P = 0.001, two-way ANOVA). However, CC mice responded better to IL-6 targeted treatment based on symptoms and weight loss (P = 0.049, two-way ANOVA).
In conclusion, the rs1800795 SNP may serve as a reliable predictor for response to IL-6-targeted treatments. Our findings may help direct the use of emerging treatments in IBD and CRC and improve outcomes for patients