185P - The Immunosuppressive Landscape of Leukemia Inhibitory Factor (LIF) in Clear Cell Renal Cell Carcinoma

Background

LIF is an interleukin 6 class cytokine that plays a crucial role in the development of many solid tumors. Herein, we identify the elusive role of LIF in clear cell renal cell carcinoma (ccRCC) and its impact on tumor immune microenvironment.

Methods

The human cancer genome atlas (TCGA) was utilized to obtain ccRCC clinicopathological and expression data. The prognostic utility of LIF expression in ccRCC was evaluated using univariate and multivariate Cox logistic regression analysis. Co-expressed genes were explored using LinkedOmics and their biological roles were identified using gene set enrichment analysis (GSEA) through KEGG pathways terminology. The immune microenvironment was evaluated using Tumor IMmune Estimation Resource (TIMER 2.0). Correlations between LIF expression and immune-related genes were obtained using the Gene Expression Profiling Interactive Analysis (GEPIA).

Results

High LIF expression is associated with shortened overall survival (HR: 1.828, 95% CI: 1.358-2.460, P < .0001) in TCGA ccRCC cohort. Multivariate Cox logistic regression analysis identified LIF expression as an independent prognostic variable (HR: 0.48, 95% CI: 0.303-0.759, P = .002). GSEA showed enrichment in IL-17, TNF, JAK-STAT and NF-kB signaling pathways besides cytokine-cytokine receptor interaction, transcriptional misregulation in cancer, complement and coagulation cascades. LIF expression is positively corelated with immunosuppressive cellular elements including Tregs (ρ = 0.14, Q = 0.012), M2 macrophages (ρ = 0.25, Q < .0001), and myeloidderived suppressor cells (ρ = 0.18, Q value < .001). In addition, LIF corelated significantly with Tregs-related genes including FOXP3 (ρ = 0.28, P < .0001), CCR8 (ρ = 0.23, P < .0001), and TGF-β (ρ = 0.38, P < .0001). M2 macrophages-related genes were also significantly corelated with LIF expression as in CD163 (ρ = 0.30, P < .0001), VSIG4 (ρ = 0.27, P < .0001), and MS4A4A (ρ = 0.24, P < .0001). Immune check points genes were also influenced by LIF expression including CTLA4 (ρ = 0.25, P < .0001) and LAG3 (ρ = 0.21, P < .0001).

Conclusions

LIF upregulation corelates with poor prognosis in ccRCC and induces an immune suppressed microenvironment.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.