Abstract
Natural autoantibodies play a crucial role in destruction of malignant tumors due to immune surveillance function. Epidermal growth factor receptor 2 (HER2) has been found to be highly expressed in a variety of epithelial tumors including oral squamous cell carcinoma (OSCC). The present study was thus undertaken to investigate the effect of anti-HER2 natural autoantibodies on OSCC. Compared with cancer-adjacent tissues, cancer tissues from OSCC patients exhibited higher HER2 expression especially in those with middle & advanced stage OSCC. Plasma anti-HER2 IgG levels examined with an enzyme-linked immunosorbent assay (ELISA) developed in-house showed differences between control subjects, individuals with oral benign tumor and patients with OSCC. In addition, anti-HER2 IgG-abundant plasma was screened from healthy donors to treat OSCC cells and to prepare for anti-HER2 intravenous immunoglobulin (IVIg). Both anti-HER2 IgG-abundant plasma and anti-HER2 IVIg could significantly inhibit proliferation and invasion of OSCC cells by inducing the apoptosis, and also regulate apoptosis-associated factors and epithelial-mesenchymal transition (EMT), respectively. Besides, the complement-dependent cytotoxicity (CDC) pathway was likely to contribute to the anti-HER2 IgG mediated inhibition of OSCC cells. After the HER2 gene was knocked down with HER2-specific siRNAs, the inhibitory effects on OSCC cell proliferation and apoptotic induction faded away. In conclusion, human plasma IgG, or IVIg against HER2 may be a promising agent for anti-OSCC therapy.
Highlights
Oral squamous cell carcinoma (OSCC) is the sixth leading cancer worldwide and accounts for approximately 90% of all oral malignant tumors (Niu et al, 2020; Zheng et al, 2021)
We found that healthy individuals had remarkably high levels of natural IgG antibodies against human vascular endothelial growth factor receptor 1 (VEGFR1) and that antiVEGFR1 IgG-abundant plasma could inhibit the proliferation of liver cancer cells (Wang et al, 2017)
Further analysis was performed to compare plasma antiHER2 IgG levels between subgroups and indicated that antiHER2 IgG levels were slightly lower in patients with oral benign tumor and early stage oral squamous cell carcinoma (OSCC) than control subjects, while plasma anti-HER2 IgG levels showed a trend toward an increase in OSCC patients at the middle & advanced stages compared with those at the early stage (Table 2)
Summary
Oral squamous cell carcinoma (OSCC) is the sixth leading cancer worldwide and accounts for approximately 90% of all oral malignant tumors (Niu et al, 2020; Zheng et al, 2021). Diverse results regarding the overexpression of HER2 in OSCC have been reported (Werkmeister et al, 2000; Fong et al, 2008; Cierpikowski et al, 2018) This highlights the importance of further investigation of HER2 in OSCC development. Small molecule inhibitors or antibodies targeting HER2 have been approved for treatment of patients with HER2-positive breast cancer, non-small cell lung cancer (NSCLC), and gastroesophageal cancer (Iqbal and Iqbal, 2014; Cameron et al, 2017; Kneissl et al, 2017; Liu et al, 2018; Okamoto et al, 2020). MAb-based immunotherapy has raised new questions about assessment of drug toxicity, the economics of cancer therapy, and resistance to treatments (Kristeleit et al, 2016; Dempsey et al, 2021). HER2-targeted medications have not been applied clinically to treat OSCC, so that there is an urgent need to develop HER2based alternative and safe therapies
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