Failure of immune response and genetic changes as a cause of recurrent squamous cell carcinoma of oral cavity

Abstract

Introduction: Recurrence and spread of cancer is the main cause of cancer-related death. But recent staging system mainly focuses on anatomic considerations, so it has limitations in reflecting host immune responses against transformed cells or different potential of individual tumors to recur or to spread. Considering carcinogenesis begins with genetic changes, finding genetic alterations of host genome can be more basic and physical way of research. Genes promoting the progression of tumor were reported in some previous studies but the importance of interactions between tumor cells and host immune system was usually neglected. Considering that oral squamous cell carcinoma arise from the epithelium of aerodigestive tract mucosa where intensive mucosal immune system functions, the role of host immune response against transformed cells gains more importance.

Methods: Patients who were diagnosed with squamous cell carcinoma of oral cavity and underwent successful surgical resection were included. Gene expression profiles were compared between recurrent and non-recurrent group of the patients in both tumor and local tumor-free lymph node samples by cDNA microarray (Selection criteria: p<0.01 or 0.05, fold difference ≥2.0 or ≤0.5). Immunohistochemical analysis of tissue samples was carried out for phenotypic analysis.

Results: Widespread immune dysfunctions in local lymph node samples of recurrent group were most distinctive features. Genes associated with antigen presentation (HLA-DPA1, CD1E), antigen recognition of T cell (CD3D, CD2, CD5), co-stimulators (CD28, B7.1) and chemotaxis of immune effectors (CCR4) were down-regulated. In tumor samples, FAS was over-expressed, which induces apoptosis of immune effectors. Genes promoting tumor progression were also identified. COX-2(=PTGS2), a well-known gene that promotes angiogenesis and cell proliferation and MMP25, a metalloproteinase known to have relation with metastasis, were over-expressed. Immunohistochemical analysis revealed that recurrent group had relatively high immuno-reactivity for tumor-promoting genes and non-recurrent group showed more obviously high immuno-reactivity for genes related with tumor immunity in local lymph node samples.

Conclusions: Our study revealed that unsuccessful clearance of migrating tumor cells in local lymph nodes could be the main cause of tumor progression and also confirmed that almost whole processes of antigen presentation, antigen recognition, subsequent immune reaction were affected. Aggressive genetic natures of tumor itself were also identified in the process of tumor recurrence and progression although it was not that obvious than their role in the initial malignant transformation suggested by previous studies.