Related Experiment Video
Updated: Feb 6, 2026
Oncogene Expression Analysis with Alterations in pH in a Pancreatic Ductal Cell Line
Published on: April 11, 2025
Elevated T Cell Immunoreceptor with Ig and ITIM Domains (TIGIT) Expression and Immune Cell Dysfunction Characterize
Shungang Zhang1, Elaina R Daniels1, Jake McGue2
1Department of Pathology & Clinical Labs, University of Michigan, Ann Arbor, Michigan.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune therapies. Limited biomarkers, such as mismatch repair proteins, have been used to identify those who may respond to immunotherapy. We identified a subset of aggressive PDACs (⁓25%) carrying mutations in the complex of proteins associated with SET1-like complex genes (CLCGs), which can be used as new biomarkers for targeted immunotherapy. In this study, we compared the immune microenvironment of PDACs harboring CLCG mutations with matched wild-type PDACs using multiplex fluorescent immunohistochemistry and computational imaging techniques. We observed that CLCG-mutant PDACs were infiltrated with fewer CD4+ T cells and antigen-presenting cells (APCs) but elevated immune checkpoint T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression on CD4+ T cells and APCs. There was no difference in the expressions of other immune checkpoints, such as programmed death-1 receptor ligand and T-cell immunoglobulin and mucin domain-containing protein 3. More CD4+ T cells near epithelial cells (tumor cells) and APCs expressed TIGIT in CLCG-mutant PDACs. Additionally, CLCG-mutant PDACs displayed a malfunctional immune cell crosstalk. Single-cell RNA-sequencing data confirmed the elevated TIGIT expression on CD4+ T cells and increased exhausted CD4+ T cells in CLCG-low PDACs. These findings uncovered the unique underlying mechanisms of immune suppression in CLCG-deficient PDACs and identified CLCG as potential biomarkers to identify those who may benefit from TIGIT-targeting immunotherapies.
Insights
COMPASS-like complex gene (CLCG) mutations identify aggressive pancreatic cancer (PDAC) resistant to immunotherapy. These mutations correlate with altered immune cell infiltration and elevated TIGIT checkpoint expression, suggesting TIGIT-targeting therapies for CLCG-mutant PDAC.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits significant resistance to current immunotherapies.
- Biomarkers for immunotherapy response in PDAC are limited, with mismatch repair proteins being a notable exception.
- A subset of aggressive PDACs (approx. 25%) harbors mutations in COMPASS-like complex genes (CLCG).
Purpose of the Study:
- To investigate the immune microenvironment of PDACs with CLCG mutations compared to wild-type PDACs.
- To identify potential new biomarkers for targeted immunotherapy in PDAC.
- To explore the role of CLCG mutations in immune suppression mechanisms within PDAC.
Main Methods:
- Multiplex fluorescent immunohistochemistry (mfIHC) was employed to analyze immune cell infiltration and checkpoint expression.
- Computational imaging techniques were utilized to quantify cellular interactions and spatial relationships.
- Single-cell RNA sequencing (scRNA-seq) was performed to confirm gene expression patterns and immune cell states.
Main Results:
- CLCG-mutant PDACs showed reduced infiltration of CD4+ T cells and antigen-presenting cells (APCs).
- Elevated expression of the immune checkpoint TIGIT was observed on CD4+ T cells and APCs in CLCG-mutant PDACs.
- CLCG-mutant PDACs exhibited impaired immune cell crosstalk and increased CD4+ T cell exhaustion.
Conclusions:
- COMPASS-like complex genes (CLCG) can serve as novel biomarkers for identifying PDAC patients who may benefit from immunotherapy.
- The findings reveal unique immune suppression mechanisms in CLCG-deficient PDAC.
- Targeting TIGIT represents a potential therapeutic strategy for CLCG-mutant pancreatic cancer.
Related Concept Videos
01:58Cell Specific Gene Expression
01:58Cell Specific Gene Expression
01:09Mutation, Gene Flow, and Genetic Drift
01:42What is Gene Expression?
Gene expression is the process in which DNA directs the synthesis of functional products, that is, proteins. Cells can regulate gene expression at various stages. It allows organisms to generate different cell types and enables cells to adapt to internal and external factors.
Genetic Information Flows from DNA to RNA to Protein
A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is made up of nucleotides and proteins consist of amino...
01:36What is Gene Expression?
01:23Compass