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Multi-omic Characterization of Pancreatic Ductal Adenocarcinoma Relates CXCR4 mRNA Expression Levels to Potential Clinical Targets
Kocher, Florian Puccini, Alberto Untergasser, Gerold Martowicz, Agnieszka Zimmer, Kai Pircher, Andreas Baca, Yasmine Xiu, Joanne Haybaeck, Johannes Tymoszuk, Piotr
Kocher, Florian
Puccini, Alberto
Untergasser, Gerold
Martowicz, Agnieszka
Zimmer, Kai
Pircher, Andreas
Baca, Yasmine
Xiu, Joanne
Haybaeck, Johannes
Tymoszuk, Piotr
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2022-11-15
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http://dx.doi.org/10.1158/1078-0432.ccr-22-0275
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.
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Florian Kocher, Alberto Puccini, Gerold Untergasser, Agnieszka Martowicz, Kai Zimmer, Andreas Pircher, Yasmine Baca, Joanne Xiu, Johannes Haybaeck, Piotr Tymoszuk, Richard M. Goldberg, Angelica Petrillo, Anthony F. Shields, Mohamed E. Salem, John L. Marshall, Michael Hall, W. Michael Korn, Chadi Nabhan, Francesca Battaglin, Heinz-Josef Lenz, Emil Lou, Su-Pin Choo, Chee-Keong Toh, Silvia Gasteiger, Renate Pichler, Dominik Wolf, Andreas Seeber; Multi-omic Characterization of Pancreatic Ductal Adenocarcinoma Relates CXCR4 mRNA Expression Levels to Potential Clinical Targets. Clin Cancer Res 15 November 2022; 28 (22): 4957–4967. https://doi.org/10.1158/1078-0432.CCR-22-0275
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American Association for Cancer Research
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Clinical Cancer Research, Vol. 28, Iss. 22
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