T-Cell Infiltration and Immune Checkpoint Expression Increase in Oral Cavity Premalignant and Malignant Disorders.

The immune cell niche associated with oral dysplastic lesion progression to carcinoma is poorly understood. We identified T regulatory cells (Treg), CD8 + effector T cells (Teff) and immune checkpoint molecules across oral dysplastic stages of oral potentially malignant disorders (OPMD). OPMD and oral squamous cell carcinoma (OSCC) tissue sections (N = 270) were analyzed by immunohistochemistry for Treg (CD4, CD25 and FoxP3), Teff (CD8) and immune checkpoint molecules (PD-1 and PD-L1). The Treg marker staining intensity correlated significantly ( p < 0.01) with presence of higher dysplasia grade and invasive cancer. These data suggest that Treg infiltration is relatively early in dysplasia and may be associated with disease progression. The presence of CD8 + effector T cells and the immune checkpoint markers PD-1 and PD-L1 were also associated with oral cancer progression ( p < 0.01). These observations indicate the induction of an adaptive immune response with similar Treg and Teff recruitment timing and, potentially, the early induction of exhaustion. FoxP3 and PD-L1 levels were closely correlated with CD8 levels ( p < 0.01). These data indicate the presence of reinforcing mechanisms contributing to the immune suppressive niche in high-risk OPMD and in OSCC. The presence of an adaptive immune response and T-cell exhaustion suggest that an effective immune response may be reactivated with targeted interventions coupled with immune checkpoint inhibition.