Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Kocher, F; Puccini, A; Untergasser, G; Martowicz, A; Zimmer, K; Pircher, A; Baca, Y; Xiu, J; Haybaeck, J; Tymoszuk, P; Goldberg, RM; Petrillo, A; Shields, AF; Salem, ME; Marshall, JL; Hall, M; Korn, WM; Nabhan, C; Battaglin, F; Lenz, HJ; Lou, E; Choo, SP; Toh, CK; Gasteiger, S; Pichler, R; Wolf, D; Seeber, A.
Multi-omic Characterization of Pancreatic Ductal Adenocarcinoma Relates CXCR4 mRNA Expression Levels to Potential Clinical Targets.
Clin Cancer Res. 2022; 28(22):4957-4967
Doi: 10.1158/1078-0432.CCR-22-0275
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- Co-Autor*innen der Med Uni Graz
- Haybäck Johannes
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- Abstract:
- PURPOSE: Chemokines are essential for immune cell trafficking and are considered to have a major impact on the composition of the tumor microenvironment. CX-chemokine receptor 4 (CXCR4) is associated with poor differentiation, metastasis, and prognosis in pancreatic ductal adenocarcinoma (PDAC). This study provides a comprehensive molecular portrait of PDAC according to CXCR4 mRNA expression levels. EXPERIMENTAL DESIGN: The Cancer Genome Atlas database was used to explore molecular and immunologic features associated with CXCR4 mRNA expression in PDAC. A large real-word dataset (n = 3,647) served for validation and further exploratory analyses. Single-cell RNA analyses on a publicly available dataset and in-house multiplex immunofluorescence (mIF) experiments were performed to elaborate cellular localization of CXCR4. RESULTS: High CXCR4 mRNA expression (CXCR4high) was associated with increased infiltration of regulatory T cells, CD8+ T cells, and macrophages, and upregulation of several immune-related genes, including immune checkpoint transcripts (e.g., TIGIT, CD274, PDCD1). Analysis of the validation cohort confirmed the CXCR4-dependent immunologic TME composition in PDAC irrespective of microsatellite instability-high/mismatch repair-deficient or tumor mutational burden. Single-cell RNA analysis and mIF revealed that CXCR4 was mainly expressed by macrophages and T-cell subsets. Clinical relevance of our finding is supported by an improved survival of CXCR4high PDAC. CONCLUSIONS: High intratumoral CXCR4 mRNA expression is linked to a T cell- and macrophage-rich PDAC phenotype with high expression of inhibitory immune checkpoints. Thus, our findings might serve as a rationale to investigate CXCR4 as a predictive biomarker in patients with PDAC undergoing immune checkpoint inhibition.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Receptors, Chemokine - administration & dosage
- Carcinoma, Pancreatic Ductal - pathology
- Pancreatic Neoplasms - pathology
- Tumor Microenvironment - genetics
- RNA, Messenger - genetics
- RNA - administration & dosage
- Receptors, CXCR4 - genetics, metabolism