Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway
Sayuri Miyauchi,
Sangwoo S. Kim,
Riley N. Jones,
Lin Zhang,
Kripa Guram,
Sonia Sharma,
Stephen P. Schoenberger,
Ezra E.W. Cohen,
Joseph A. Califano,
Andrew B. Sharabi
Affiliations
Sayuri Miyauchi
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
Sangwoo S. Kim
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
Riley N. Jones
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
Lin Zhang
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
Kripa Guram
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
Sonia Sharma
La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Stephen P. Schoenberger
La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Ezra E.W. Cohen
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
Joseph A. Califano
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA; Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA 92037, USA
Andrew B. Sharabi
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA; Corresponding author
Summary: The role that human papillomavirus (HPV) oncogenes play in suppressing responses to immunotherapy in cancer deserves further investigation. In particular, the effects of HPV E5 remain poorly understood relative to E6 and E7. Here, we demonstrate that HPV E5 is a negative regulator of anti-viral interferon (IFN) response pathways, antigen processing, and antigen presentation. Using head and neck cancer as a model, we identify that E5 decreases expression and function of the immunoproteasome and that the immunoproteasome, but not the constitutive proteasome, is associated with improved overall survival in patients. Moreover, immunopeptidome analysis reveals that HPV E5 restricts the repertoire of antigens presented on the cell surface, likely contributing to immune escape. Mechanistically, we discover a direct interaction between E5 and stimulator of interferon genes (STING), which suppresses downstream IFN signaling. Taken together, these findings identify a powerful molecular mechanism by which HPV E5 limits immune detection and mediates resistance to immunotherapy.
