Transcriptional analysis highlights three distinct immune profiles of high-risk oral epithelial dysplasia

Abstract

Oral potentially malignant disorders (OPMD) are precursors of oral squamous cell carcinoma (OSCC), and the presence of oral epithelial dysplasia (OED) in OPMD confers an increased risk of malignant transformation. Emerging evidence has indicated a role for the immune system in OPMD disease progression; however, the underlying immune mechanisms remain elusive. In this study, we used immune signatures established from cancer to delineate the immune profiles of moderate and severe OED, which are considered high-risk OPMD. We demonstrated that moderate and severe OEDs exhibit high lymphocyte infiltration and upregulation of genes involved in both immune surveillance (major histocompatibility complex-I, T cells, B cells and cytolytic activity) and immune suppression (immune checkpoints, T regulatory cells, and tumor-associated macrophages). Notably, we identified three distinct subtypes of moderate and severe OED: immune cytotoxic, non-cytotoxic and non-immune reactive. Active immune surveillance is present in the immune cytotoxic subtype, whereas the non-cytotoxic subtype lacks CD8 immune cytotoxic response. The non-immune reactive subtype showed upregulation of genes involved in the stromal microenvironment and cell cycle. The lack of T cell infiltration and activation in the non-immune reactive subtype is due to the dysregulation of CTNNB1, PTEN and JAK2. This work suggests that moderate and severe OED that harbor the non-cytotoxic or non-immune reactive subtype are likely to progress to cancer. Overall, we showed that distinct immune responses are present in high-risk OPMD, and revealed targetable pathways that could lead to potential new approaches for non-surgical management of OED.

A digital score of peri-epithelial lymphocytic activity predicts malignant transformation in oral epithelial dysplasia

“…Gan et al . 40 has also shown similar finding of PELs using the RNA sequencing of the immune infiltrating sites within the moderate and severe OED. They have stated in their work that the lack of CD8 T-cells in non-cytotoxic subtype and non-immune reactive subtype can lead to progression in moderate and severe dysplasia.…”

“…For progression free survival, we analysed the clinical, pathological, and nuclear features and found that apart from binary grading in OED, the variation in basal and epithelial layer NC to be associated with improved PFS while minimum number of in basal layer NC, epithelial layer NC and PEL to be associated with increased risk of malignant transformation or poor survival. Gan et al 40 has also shown similar finding of PELs using the RNA sequencing of the immune infiltrating sites within the moderate and severe OED. They have stated in their work that the lack of CD8 Tcells in non-cytotoxic subtype and non-immune reactive subtype can lead to progression in moderate and severe dysplasia.…”

“…However, in order to verify the significance of these features further we require more data to validate these features for their prognostic significance for malignancy. It has also been reported in the literature that the PELs can play an important role in transforming dysplasia into carcinoma 40 . There is a possible explanation for transformation, that the epithelium is affected by the PEL.…”

The preliminary exploration of immune microenvironment in oral leukoplakia concomitant with oral submucosal fibrosis: A comparative immunohistochemical study

“…2 To resist this cancer-promoting effect, the immune microenvironmental with immune surveillance features has been elucidated in OLK with epithelial dysplasia. 8,19 In this study, epithelial dysplasia occurred in all samples of OLK and OLK concomitant with OSF, but not observed in all OSF samples. Thus, immune cell infiltration in both OLK and OLK concomitant with OSF was higher than that in OSF.…”

“…Epithelial dysplasia is a common risk factor for malignant transformation of OLK 2 . To resist this cancer‐promoting effect, the immune microenvironmental with immune surveillance features has been elucidated in OLK with epithelial dysplasia 8,19 . In this study, epithelial dysplasia occurred in all samples of OLK and OLK concomitant with OSF, but not observed in all OSF samples.…”