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Protein-level profiling of TIGIT axis components in human PDAC reveals immune-suppressive expression patterns
D Quatannens1, Y Verhoeven1, S van der Heijden1
1Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
Purpose:
In pancreatic ductal adenocarcinoma (PDAC), immune checkpoint inhibitors have shown limited efficacy, and the role of the TIGIT axis remains underexplored. This study aimed to characterize TIGIT axis components on protein level and their relationship to PD-1/PD-L1 expression in matched blood and tumor samples from PDAC patients to identify immunosuppressive mechanisms and fuel future strategies for immune checkpoint co-targeting in PDAC patients.
Experimental Design:
Fresh tumor and peripheral blood samples were collected from PDAC patients undergoing surgical resection. Flow cytometry was performed on tumor-infiltrating lymphocytes and PBMCs to assess expression of TIGIT, DNAM-1, TACTILE, and PD-1. Ligands CD111, CD112, CD113, and CD155 were analyzed using immunohistochemistry. Additional RNA expression analysis (TCGA/GTEx) was used to evaluate ligand distribution and gene expression profiles.
Results:
TIGIT was highly upregulated on intratumoral CD8⁺ T cells and regulatory T cells, frequently co-expressed with PD-1. DNAM-1 expression was significantly reduced in tumors. However, contrasting pattern emerges with Tregs, which uniquely upregulate DNAM-1 in the PDAC TME. In addition, CD112 and CD155 were broadly expressed, including novel stromal CD112 localization. NK cells were nearly absent intratumorally, correlating with DNAM-1 downregulation.
Conclusions:
Our findings identify TIGIT as a promising immunotherapeutic target in PDAC and suggest that dual checkpoint blockade (TIGIT/PD-1), alongside restoration of DNAM-1 signaling, may overcome immune suppression. These results provide mechanistic rationale to inform future clinical trials in PDAC.
Insights
Immune checkpoint TIGIT is upregulated in pancreatic cancer, suggesting dual TIGIT/PD-1 blockade may overcome immune suppression. Restoring DNAM-1 signaling is also crucial for effective immunotherapy in PDAC patients.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Immune checkpoint inhibitors show limited efficacy in pancreatic ductal adenocarcinoma (PDAC).
- The role of the TIGIT immune checkpoint axis in PDAC is underexplored.
- Understanding immunosuppressive mechanisms is key for developing effective PDAC therapies.
Purpose of the Study:
- To characterize TIGIT axis components on protein level in PDAC.
- To investigate the relationship between TIGIT and PD-1/PD-L1 expression.
- To identify strategies for immune checkpoint co-targeting in PDAC.
Main Methods:
- Analysis of matched blood and tumor samples from PDAC patients.
- Flow cytometry to assess TIGIT, DNAM-1, TACTILE, and PD-1 expression on immune cells.
- Immunohistochemistry for ligand analysis (CD111, CD112, CD113, CD155).
- RNA expression analysis (TCGA/GTEx) for ligand distribution and gene profiles.
Main Results:
- TIGIT was highly upregulated on intratumoral CD8+ T cells and regulatory T cells (Tregs), often co-expressed with PD-1.
- DNAM-1 expression was reduced in tumors, but uniquely upregulated on Tregs within the PDAC tumor microenvironment (TME).
- CD112 and CD155 ligands were broadly expressed, with novel stromal CD112 localization.
- Intratumoral NK cells were scarce, correlating with DNAM-1 downregulation.
Conclusions:
- TIGIT is a promising immunotherapeutic target in PDAC.
- Dual checkpoint blockade (TIGIT/PD-1) combined with DNAM-1 signaling restoration may overcome PDAC immune suppression.
- These findings provide a mechanistic basis for future clinical trials in PDAC.
