Distinctive tumor biology of oral squamous cell carcinoma associated with oral submucous fibrosis and its suppressive immune microenvironment

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies in Southern and Southeastern Asia, and in the Hunan region of China, where betel nut chewing is prevalent. The prognosis of OSCC with oral submucous fibrosis (OSF), caused by areca nut use, remains debated. This study aimed to determine whether OSCC associated with OSF exhibits distinct tumor biological behaviors compared to OSCC without OSF, and to explore the tumor immune microenvironment, specifically focusing on the expression of Th17/Treg cells and the PD-1/PD-L1 axis. METHODS: -test); survival/log survival/hazard functions were plotted to compare survival probabilities, stratified by sex, age, tumor location, stage (early/advanced, TNM), and habits (betel quid, smoking, alcohol). A subgroup of 88 patients (44 each) had immunohistochemical analysis for Th17/Treg and PD-1/PD-L1 expression. RESULTS: OSCC with OSF primarily affected the tongue and buccal mucosa, occurring in younger patients (median age 48 vs. 55 years). Recurrence was higher in OSF-associated OSCC (27.56% vs. 19.73%). Overall Survival (OS) rates for OSCC with OSF were 94.25% (1-year OS), 49.82% (3-year OS), and 41.23% (5-year OS), compared to 94.82% (1-year OS), 56.58% (3-year OS), and 47.92% (5-year OS) in non-OSF cases. A subgroup of 88 patients (44 each) had immunohistochemical analysis for the expression of IL-17 (a marker of Th17 cells) and Foxp3 (a marker of Treg cells), as well as PD-1/PD-L. Immune profiling showed elevated IL-17, Treg cells, PD-L1, and PD-1 in OSF-associated OSCC. CONCLUSION: OSCC with OSF displays more aggressive tumor biological behavior and worse prognosis, which contributed by a more suppressive immune microenvironment marked by elevated levels of IL-17, Treg cells, and PD-1/PD-L1 expression. These results highlight the need for tailored treatment approaches in managing OSCC in patients with OSF.