A Four-Chemokine Signature Is Associated with a T-cell-Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer PMID: 31964786

RQC and Longevity Regulation

2026-09-03

A Four-Chemokine Signature Is Associated with a T-cell-Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer

Clin Cancer Res. 2020 Apr 15;26(8):1997-2010. doi: 10.1158/1078-0432.CCR-19-2803.

Joan M Romero ¹ ² , Barbara Grünwald ³ , Gun-Ho Jang ² , Prashant P Bavi ¹ ² , Aaditeya Jhaveri ² , Mehdi Masoomian ⁴ , Sandra E Fischer ¹ ² ⁴ , Amy Zhang ² , Robert E Denroche ² , Ilinca M Lungu ⁵ , Angela De Luca ⁵ , John M S Bartlett ⁵ , Jing Xu ⁶ , Niandong Li ⁷ , Sharon Dhaliwal ⁷ , Sheng-Ben Liang ⁷ , Dianne Chadwick ⁷ , Foram Vyas ³ , Peter Bronsert ⁸ ⁹ , Rama Khokha ³ , Tracy L McGaha ³ ¹⁰ , Faiyaz Notta ² , Pamela S Ohashi ³ ¹⁰ , Susan J Done ¹ ⁴ , Grainne M O'Kane ² ¹¹ , Julie M Wilson ² , Jennifer J Knox ² ¹¹ , Ashton Connor ² , Yifan Wang ¹² ¹³ , George Zogopoulos ¹² ¹³ , Steven Gallinger ¹⁴ ² ¹¹ ¹⁵ ¹⁶ ¹⁷

Affiliations

1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
2. PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
3. Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
4. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
5. Diagnostic Development, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
6. Drug Development Program Biomarker Laboratory, University Health Network, University of Toronto, Toronto, Ontario, Canada.
7. UHN Biobank, University Health Network, Toronto, Ontario, Canada.
8. Tumorbank Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
9. Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
10. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
11. Wallace McCain Centre of Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
12. The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
13. The Goodman Cancer Research Centre of McGill University, Montréal, Québec, Canada.
14. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [email protected].
15. Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
16. Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
17. Hepatobilliary Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.

Abstract

Purpose: The molecular drivers of antitumor immunity in Pancreatic Ductal Adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.

Experimental design: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA Sequencing (RNA-seq), and mutational burden by whole-genome Sequencing.

Results: Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8⁺ T-cell infiltration (P < 0.001). Expression of this "4-chemokine signature" positively correlated with transcriptional metrics of T-cell activation (ZAP70, Itk, and IL2RB), cytolytic activity (GZMA and PRF1), and Immunosuppression (PDL1, PD1, CTLA4, Tim3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked Tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell-inflamed phenotype across primary PDAC and PDAC liver metastases.

Conclusions: A conserved 4-chemokine signature marks resectable and metastatic PDAC Tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.