A four-chemokine signature is associated with a T-cell- inflamed phenotype in primary and metastatic pancreatic cancer

Joan M. Romero, Barbara Grünwald, Gun Ho Jang, Prashant P. Bavi, Aaditeya Jhaveri, Mehdi Masoomian, Sandra E. Fischer, Amy Zhang, Robert E. Denroche, Ilinca M. Lungu, Angela De Luca, John M.S. Bartlett, Jing Xu, Niandong Li, Sharon Dhaliwa, Sheng Ben Liang, Dianne Chadwick, Foram Vyas, Peter Bronsert, Rama KhokhaTracy L. McGaha, Faiyaz Notta, Pamela S. Ohashi, Susan J. Done, Grainne M. O'Kane, Julie M. Wilson, Jennifer J. Knox, Ashton Connor, Yifan Wang, George Zogopoulos, Steven Gallinger

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1997-2010
Number of pages14
JournalClinical Cancer Research
Volume26
Issue number8
DOIs
StatePublished - Apr 15 2020

ASJC Scopus subject areas

  • Medicine(all)

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