1. HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer
- Author
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Miyauchi, Sayuri, Sanders, P Dominick, Guram, Kripa, Kim, Sangwoo S, Paolini, Francesca, Venuti, Aldo, Cohen, Ezra EW, Gutkind, J Silvio, Califano, Joseph A, and Sharabi, Andrew B
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Sexually Transmitted Infections ,Rare Diseases ,Dental/Oral and Craniofacial Disease ,Vaccine Related ,Cervical Cancer ,Cancer ,Infectious Diseases ,HIV/AIDS ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Animals ,Antigen Presentation ,Antineoplastic Agents ,Immunological ,Antineoplastic Combined Chemotherapy Protocols ,B7-H1 Antigen ,Cell Line ,Tumor ,Chemoradiotherapy ,Cohort Studies ,Disease Models ,Animal ,Down-Regulation ,Drug Resistance ,Neoplasm ,Female ,Gene Expression Regulation ,Neoplastic ,HEK293 Cells ,Head and Neck Neoplasms ,Healthy Volunteers ,Histocompatibility Antigens Class II ,Human papillomavirus 16 ,Humans ,Male ,Mice ,Middle Aged ,Oncogene Proteins ,Viral ,Papillomavirus Infections ,RAW 264.7 Cells ,RNA-Seq ,Rimantadine ,Squamous Cell Carcinoma of Head and Neck ,Young Adult ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti-PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti-PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. SIGNIFICANCE: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/4/732/F1.large.jpg.
- Published
- 2020