Abstract

Introduction: Patients with oral leukoplakia diagnosed with moderate-severe oral epithelial dysplasia (OED) have an increased risk of developing oral cancer. However, chemoprevention agents targeting epithelial cells are ineffective in preventing malignant transformation and disease recurrence. Emerging evidence indicates that host immunity can impact premalignant disease progression, but the immune profile of oral leukoplakia has not been studied. In this study, we characterized the immune profile of high-risk oral leukoplakia with a long-term aim of identifying immunotherapeutic strategies to intercept cancer development. Methods: The immune profile of moderate-severe OED was determined by transcriptomic analysis of 125 immune signatures reported in cancer. To determine the utility of a cancer vaccine targeting MAGED4B, we evaluated MAGED4B expression by immunohistochemistry on oral leukoplakia tissues. Then, in-vitro T cell-based immunogenicity studies were performed using patients’ blood samples to evaluate antigen-specific immune responses. Results: Immune profiling demonstrated the induction of both immune surveillance and immune suppression mechanisms in moderate-severe OED. Notably, three distinct immune subtypes were identified: (1) immune cytotoxic; (2) non-cytotoxic; and (3) non-immune reactive. Patients progressed to cancer appear to lack cytotoxic T cells responses, suggesting that restoring T cell immunity via cancer vaccine may intercept malignant development. Next, we evaluated the feasibility of activating patients’ immune responses using a cancer vaccine targeting MAGED4B. We demonstrated that moderate-severe OED significantly over-expressed MAGED4B. Our T cell-based immunogenicity studies showed that MAGED4B-specific CD8⁺ T cells could be expanded in-vitro and become activated as indicated by increased interferon gamma secretion and CD38 expression. Importantly, these CD8⁺ T cells demonstrated antigen-specific killing of tumour cells expressing MAGED4B.  Conclusion: Our series of studies demonstrated that discrete immune responses are present in high-risk leukoplakia, and antigen-specific immune response can be harnessed to induce cytotoxic responses in these lesions. 

Keywords: Oral leukoplakia, Immune profile, Oral epithelial dysplasia, Cancer vaccine