STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

Abstract

Objectives The intracellular DNA sensor stimulator of interferon genes (STING) has recently been shown to play a vital role in anti-viral and anti-tumor immune responses stimulating cytokine production. While human papillomavirus (HPV) is a causative agent for a subset of head and neck squamous cell carcinoma (HNSCC) with unique etiology and clinical outcome, how the STING pathway is regulated in a virus-induced tumor microenvironment is not well understood. Since STING inactivation likely reflects immunoescape via innate immunity, we hypothesized that its restoration would improve efficacy of the immune modulatory monoclonal antibody (mAb), cetuximab. Materials and methods We correlated STING protein expression with clinical parameters by immunohistochemistry (n = 106) and its mRNA expression from The Cancer Genome Atlas (TCGA) in HNSCC tissue specimens. STING protein expression was tested for association with cancer-specific survival (CSS). We further examined the impact of STING activation on cetuximab-mediated immunity using an in vitro NK:DC:tumor cells co-culture system. Results In this study, we found that expression of STING both at the protein and mRNA level was higher in HPV positive (HPV+) specimens but unrelated to TNM stage or cancer-specific survival. Our in vitro studies verified that STING activation enhanced cetuximab mediated NK cell activation and DC maturation. Conclusion Our findings suggest a novel role of STING in HPV-related carcinogenesis, in which activation of the STING signaling pathway may facilitate anti-tumor response in HNSCC patients, particularly in combination with therapeutic monoclonal antibodies (mAbs) such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor.

cGAS-STING responses are dampened in high-risk HPV type 16 positive head and neck squamous cell carcinoma cells

“…1b). Consistent with previous findings [15], Only transfection of HPV-SCC1 cells resulted in a robust type I IFN induction as early as 6h (Fig. 1c).…”

“…1c). Consistent with previous observations [15], SCC90 cells responded poorly to 2'3'-cGAMP (Fig. 1c).…”

“…The role of HPV 16E7 in antagonising cGAS-STING responses have yet to be addressed, let alone in the context of HNSCCs. Interestingly, STING is highly expressed in advanced HPV+, not in HPV-, HNSCC tumours [13][14][15]. Importantly, STING is expressed by basal cells in the oral mucosa, which are a key target for HPV infection, and expression is maintained in these cells through HPV+ dysplastic progression [13].…”

“…Other than NOKs, all the other tested HNSCC cells used in this study have nongingival origins [22]. This could explain why the cGAS-STING machinery is intact in these cells and therefore not surprising to find STING highly expressed in HPV+ HNSCC patient tumours from this anatomical site[13][14][15].To test the ability of HNSCC cells to respond to cGAS-STING stimulation, cells were transfected with salmon sperm DNA (S.S. DNA), a known cGAS-STING activator[23].…”

Combined Effect of HPV and Several Gene SNPs in Laryngeal Cancer

“…Vermorken JB. et al and Lu S. et al study [41,42] showed that Canter immunotherapy could be applied together with chemotherapy for HNSCC patients according to HPV status, and further studies of the new biomarkers-immunological, genetic, or molecular-are needed to be initiated to provide novel targets for improvement of HPV associated HNSCC patient therapy. In addition, markers to identify HPV-positive laryngeal cancer patients with improved prognosis are emerging [43].…”