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Updated: Aug 13, 2025
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition
Hayden Pearce1, Wayne Croft1,2, Samantha M Nicol1
1Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.
Insights
Pancreatic cancer T cells show exhaustion markers like PD-1 and TIGIT. Dual blockade of these checkpoints may improve immunotherapy responses in pancreatic ductal adenocarcinoma (PDAC) patients.
Area of Science:
- Immunology
- Oncology
- Translational Medicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with limited success of current immunotherapies.
- Understanding the tumor immune microenvironment (TME) is crucial for improving PDAC treatment strategies.
Purpose of the Study:
- To characterize T-cell populations within the PDAC tumor microenvironment.
- To investigate the potential of dual immune checkpoint blockade for PDAC immunotherapy.
Main Methods:
- Utilized cytometry by time of flight (CyTOF) and single-cell RNA sequencing to analyze tumor-infiltrating T cells.
- Assessed the expression of immune checkpoint receptors (PD-1, TIGIT) and their ligands in PDAC.
Main Results:
- T cells were the dominant immune cell type in PDAC tumors.
- Identified significant populations of CD4+ Th17 and regulatory T cells, alongside CD8+ tissue-resident memory (TRM) T cells expressing PD-1 and TIGIT.
- Observed co-localization of PD-1/TIGIT ligands with exhausted CD8+ T cells in ectopic lymphoid structures.
- Demonstrated that combined anti-PD-1 and anti-TIGIT blockade boosts T-cell IFNγ secretion and proliferation.
Conclusions:
- The PDAC TME is rich in exhausted CD8+ TRM cells expressing PD-1 and TIGIT.
- Combinatorial blockade of PD-1 and TIGIT presents a promising therapeutic strategy for PDAC immunotherapy.
