Abstract 1581: Colony-stimulating factor-1 receptor as a potential therapeutic target in pancreatic ductal adenocarcinoma

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis, rising incidence and suffers from limited existing treatment options. Currently, salient features of PDAC are being investigated that can potentially predict immunotherapy outcomes, to identify small patient populations that can benefit from such strategies. Preliminary studies show that colony-stimulating factor-1 receptor (CSF1R), a surface receptor tyrosine kinase that drives survival, function, proliferation and differentiation of several myeloid lineage cell types can be a potentially interesting target for combination immunotherapy. Methods: PDAC patients from the TCGA PanCancer Atlas were stratified into CSF1Rhi and CSF1Rlo cohorts and clinically relevant characteristics were compared between the two. The mRNA expression of CSF1R and immunological markers of interest were evaluated and Gene Set Enrichment Analysis (GSEA) was run on the two groups to analyze differential expression of gene sets. Results: mRNA expression z-scores were used to classify 129 patient samples in the TCGA PanCancer Atlas dataset into CSF1Rhi (z-score>1, n=20) and CSF1Rlo (z-score<0, n=109) cohorts. Both have similar disease staging, MSI MANTIS scores, tumor mutation burden, median diagnosis age, sex and race distribution. However, the CSF1Rhi cohort has a distinct, non-conventional PDAC driver gene mutation profile (genomic alteration frequencies in CSF1Rhi vs CSF1Rlo cohorts respectively: a) KRAS: 30% vs 73% b) CDKN2A: 15% vs 57% and c) SMAD4: 5% vs 42%) (p-value<0.01 for each). CSF1R correlates with markers of CD8+ T-cell function (R2 values: CD8A: 0.683, GZMB: 0.508, PRF1: 0.673), CD8+ T-cell infiltration (CXCL9: 0.596, CXCL10: 0.483, CCL5: 0.666) and expression of immune checkpoint genes (PDCD1: 0.602, CD274: 0.544, CTLA4: 0.613). CD8A, GZMB, PRF1, CXCL9, CXCL10, CCL5, PDCD1, CD274, CTLA4 are significantly upregulated in the CSF1Rhi group (log2Fold changes respectively: 2.07, 1.57, 1.48, 2.51, 1.71, 1.75, 1.63, 1.34, 1.80). GSEA against the hallmark gene set database shows that KRAS signaling, Inflammatory response, IL6 JAK STAT3 and Interferon-gamma signaling are significantly upregulated in the CSF1R high patient group (FDR q-value <0.01 for each). Conclusion: Preliminary in silico analysis suggests that PDAC patients with higher levels of CSF1R may be more immune infiltrated. Future studies will evaluate the potential of CSF1R as a biomarker to identify an immune infiltrated subset of PDAC patients ex vivo and the mechanism of immune infiltration in CSF1Rhi PDACs in vivo. Citation Format: Somak Chaudhuri, Dustin A. Deming, Cheri A. Pasch, Katherine A. Johnson, Chelsie K. Sievers, Philip B. Emmerich. Colony-stimulating factor-1 receptor as a potential therapeutic target in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1581.