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Updated: Mar 20, 2026
Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Increased LAG-3, TIM-3, and IDO1 Expression Is Associated With Oral Squamous Cell Carcinoma in Never Smokers and
Mathias Fiedler1,2, Alisa Off1,3, Jonas Eichberger1,2
1Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany.
Background:
Immune checkpoints such as, LAG-3, TIM-3, and IDO1 have emerged as potential therapeutic targets beyond PD-1/PD-L1 blockade. Their expression patterns in oral squamous cell carcinoma, especially among patients without smoking or alcohol exposure, remain poorly understood.
Methods:
Immunohistochemical expression of LAG-3, TIM-3, and IDO1 was examined in 130 oral squamous cell carcinoma specimens. Expression levels were correlated with clinicopathological features, immune infiltration (CD4+, CD8+, FoxP3+, CD1a+), PD-1/PD-L1 status, and smoking and drinking history. Tumors co-expressing all checkpoints (LAG-3+/TIM-3+/IDO1+/PD-L1+) were classified as "comprehensive checkpoint-positive."
Results:
High LAG-3, TIM-3, and IDO1 expression was significantly associated with never-smoking/never-drinking status (p ≤ 0.039) and increased CD4+, CD8+, and FoxP3+ T-cell densities (p ≤ 0.015). All markers showed strong correlations with PD-1/PD-L1 and with each other (p ≤ 0.002). The comprehensive checkpoint-positive phenotype occurred in 16.8% of cases, more often in never-smoking/never-drinking patients (p = 0.011), females (p = 0.026), and well-differentiated tumors (p = 0.007).
Conclusion:
Co-expression of LAG-3, TIM-3, and IDO1 characterizes an immune-active but potentially exhausted microenvironment, particularly in never-smoking, never-drinking oral squamous cell carcinoma. This pattern may define an immunologically distinct subtype with possible relevance for combinatorial immunotherapy approaches.
Insights
Immune checkpoints LAG-3, TIM-3, and IDO1 are co-expressed in oral squamous cell carcinoma, especially in never-smokers. This suggests a distinct immune subtype relevant for combination immunotherapies.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Immune checkpoints like LAG-3, TIM-3, and IDO1 are emerging therapeutic targets in cancer, beyond PD-1/PD-L1 blockade.
- Understanding their expression in oral squamous cell carcinoma (OSCC), particularly in non-smokers/non-drinkers, is crucial for targeted therapies.
Purpose of the Study:
- To investigate the expression patterns of LAG-3, TIM-3, and IDO1 in OSCC.
- To correlate these checkpoint expressions with clinicopathological features, immune infiltration, and PD-1/PD-L1 status.
- To identify a 'comprehensive checkpoint-positive' phenotype and its clinical relevance.
Main Methods:
- Immunohistochemistry was used to analyze LAG-3, TIM-3, and IDO1 expression in 130 OSCC specimens.
- Expression levels were correlated with patient data, including smoking/drinking history and immune cell infiltration (CD4+, CD8+, FoxP3+, CD1a+).
- PD-1/PD-L1 status and a 'comprehensive checkpoint-positive' phenotype (co-expression of all markers) were assessed.
Main Results:
- High expression of LAG-3, TIM-3, and IDO1 was significantly associated with never-smoking/never-drinking status and increased CD4+, CD8+, and FoxP3+ T-cell densities.
- All three markers strongly correlated with PD-1/PD-L1 status and with each other.
- The comprehensive checkpoint-positive phenotype was observed in 16.8% of cases, more frequently in never-smokers/never-drinkers, females, and well-differentiated tumors.
Conclusions:
- Co-expression of LAG-3, TIM-3, and IDO1 defines an immune-active yet potentially exhausted tumor microenvironment in OSCC.
- This phenotype is particularly prominent in never-smoking, never-drinking OSCC patients, suggesting an immunologically distinct subtype.
- This distinct subtype may hold significant implications for developing novel combinatorial immunotherapy strategies.
