期刊
HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK
卷 41, 期 8, 页码 2591-2601出版社
WILEY
DOI: 10.1002/hed.25726
关键词
cetuximab; head and neck cancer; HLA; immunogenomics; NK cells
资金
- Mosites Initiative for Personalized H&N Cancer Therapy (RLF)
- National Institutes of Health [P50 CA097190-13, R01 CA206517-02]
- AHNS Pilot (DLF)
Background Mechanisms of resistance to immune-modulating cancer treatments are poorly understood. Using a novel cohort of patients with head and neck squamous cell carcinoma (HNSCC), we investigated mechanisms of immune escape from epidermal growth factor receptor-specific monoclonal antibody (mAb) therapy. Methods HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole-exome sequencing. Expression of killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen-C (HLA-C) and the effect of KIR blockade were assessed in HNSCC cell lines. Results Nonresponders to cetuximab had an increased rate of mutations in HLA-C compared to responders and HNSCC tumors (n = 528) in The Cancer Genome Atlas (P < 0.00001). In vitro, cetuximab-activated natural killer (NK) cells induced upregulation of HLA-C on HNSCC cells (P < 0.01) via interferon gamma. Treatment of NK cells with the anti-KIR mAb lirilumab increased killing of HNSCC cells (P < 0.001). Conclusions Alterations in HLA-C may provide a mechanism of immune evasion through disruption of NK activation.
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