PO-425 Combined administration of anti-IL6 and anti-PD-L1 antibodies prevents ketogenic failure, reduces tumour progression, and increases overall survival in an autochthonous murine pancreatic cancer model

Abstract

Introduction: Tumour associated IL-6 downregulates hepatic ketogenesis and thus predisposes to metabolic stress during caloric restriction associated with cachexia. Stress-induced glucocorticoids are immune suppressive and can cause failure of cancer immunotherapy. Here, we investigate if this convergence of host metabolism and anti-tumour immunity offers a target for combination therapy with anti-IL-6 and anti-PD-L1 antibodies. Materials and methods: Combined anti-IL-6 and anti-PD-L1 antibodies (n = 13) or equimolar control antibodies (n = 12) were administered to mice bearing autochthonous pancreatic cancer (KPC: KrasLSL.G12D/+; p53R172H/+; Pdx-Cre/+). Groups were matched and all mice received 1 dose of gemcitabine. Tumour volumes were monitored by ultrasound. Body weight and food intake were recorded and the biochemical profile of mice was characterized. For statistical analysis, differences between groups were determined using an unpaired two-tailed Student's t-test. Overall survival (OS) was analysed using the Kaplan-Meier method and by applying Log-rank (Mantel-Cox) statistics. Correlation between IL-6-JAK-STAT-3 pathway and OS of patients from The Cancer Genome Atlas (TCGA) database was examined. Association of IL6 mRNA expression levels with OS was assessed in all cancer patients as well as specifically in patients with pancreatic cancer. Results: OS increased significantly in anti-IL-6 and anti-PD-L1 treated mice compared to control mice (OS: 25 days vs. 11 days, p = 0.04). Day 7 measurements revealed delayed tumour progression in the combination immunotherapy cohort (volume increase in %: 118 +/- 5.4 vs. 138 +/- 5.6, p = 0.02). The combined analysis of expression from 55505 transcripts from 9345 patients using GSEA identified an association between IL-6 pathway transcription and shorter OS (p < 0.0001). IL-6 high expression significantly decreases OS in all cancer patients (p = 2.8E-15), including patients with PDAC (p = 0.048). Conclusions: Combination treatment with anti-IL-6 and anti-PD-L1 antibodies significantly increased OS and slowed tumour growth in an autochthonous mouse model of pancreatic cancer. The results of our work provide further justification to explore this treatment combination in cachectic patients with cancer associated elevation of IL-6.