Increased LAG-3, TIM-3, and IDO1 Expression Is Associated With Oral Squamous Cell Carcinoma in Never Smokers and Never Drinkers.

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.