HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer

Cancer Res. 2020 Feb 15;80(4):732-746. doi: 10.1158/0008-5472.CAN-19-1771. Epub 2019 Dec 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antigen Presentation / drug effects
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor / transplantation
  • Chemoradiotherapy / methods
  • Cohort Studies
  • Disease Models, Animal
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / therapy*
  • Head and Neck Neoplasms / virology
  • Healthy Volunteers
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Human papillomavirus 16 / isolation & purification
  • Human papillomavirus 16 / metabolism
  • Human papillomavirus 16 / pathogenicity
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Oncogene Proteins, Viral / antagonists & inhibitors
  • Oncogene Proteins, Viral / metabolism*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / therapy*
  • Papillomavirus Infections / virology
  • RAW 264.7 Cells
  • RNA-Seq
  • Rimantadine / pharmacology*
  • Rimantadine / therapeutic use
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Squamous Cell Carcinoma of Head and Neck / immunology
  • Squamous Cell Carcinoma of Head and Neck / therapy*
  • Squamous Cell Carcinoma of Head and Neck / virology
  • Young Adult


  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Histocompatibility Antigens Class II
  • Oncogene Proteins, Viral
  • oncogene protein E5, Human papillomavirus type 16
  • Rimantadine