The membrane-associated ubiquitin ligase MARCHF8 degrades MHC-I in HPV-positive head and neck cancer for immune evasion
Abstract
The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed as a mechanism for cancer immune evasion. Nevertheless, the mechanism is poorly understood. We report here that membrane-associated RING-CH-type finger 8 (MARCHF8), upregulated by human papillomavirus (HPV), ubiquitinates and degrades MHC-I in HPV-positive head and neck cancer (HPV+ HNC). Inhibiting MARCHF8 restores MHC-I levels on HPV+ HNC cells, suppresses tumor growth, and increases the infiltration of natural killer (NK) and T cells in the tumor microenvironment. Furthermore, Marchf8 knockout markedly increases cross talk between cytotoxic NK cells and CD8 + T cells with macrophages and enhances the tumor-killing activity of CD8 + T cells. Interestingly, Marchf8 knockout, in combination with anti-PD-1 treatment, further enhances tumor suppression and increases NK and T cell infiltration in mice bearing immune checkpoint inhibitor–refractory tumors. Our findings suggest that MARCHF8 could be a promising target for immunotherapy for HPV+ HNC patients.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Mohamed I. Khalil
Department of Microbiology, Genetics, and Immunology, Michigan State University
Jie Wang
State Key Laboratory of Molecular Oncology, Beijing Key Laboratory, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences Beijing China
Lexi Vu
Department of Microbiology, Genetics, and Immunology, Michigan State University
Canchai Yang
Department of Microbiology, Genetics, and Immunology Michigan State University
Congcong Yin
Key Lab of Functional Polymers for Sustainability of Jiangsu, School of Energy and Environment
Smriti Chadha
Department of Microbiology, Genetics, and Immunology, Michigan State University
Harrison Nabors
Department of Microbiology, Genetics, and Immunology, Michigan State University
Daniel Vocelle
Department of Pharmacology and Toxicology, Michigan State University
Danielle G. May
Enabling Technologies, Sanford Research
Rachel J. Chrisopulos
Enabling Technologies, Sanford Research
Craig C. Welbon
Cancer Biology and Immunotherapies Group, Sanford Research
Li Zhou
Kyle J. Roux
Enabling Technologies, Sanford Research
William C. Spanos
Cancer Biology and Immunotherapies Group, Sanford Research
Matthew P. Bernard
Department of Pharmacology and Toxicology, Michigan State University
Qing-Sheng Mi
Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health
Dohun Pyeon
Department of Microbiology, Genetics, and Immunology Michigan State University