Authors
Lexi Vu, Nicholas S Giacobbi, Mohamed I Khalil, Canchai Yang, William J Eckerman, Evelyn D Gomez Recinos, Johnathon D Garber, Abigail Z Bennett, Bryttan Adams, Hyomin Son, Prerna Chahal, Dara M Villa, Tanisha Srivastava, Katie R Martin, Craig C Welbon, Caitlin S Williamson, William C Spanos, Jeffrey P MacKeigan, Andrew J Olive, Dohun Pyeon
Published in
Cancer immunology research. Sep 28, 2026. Epub Sep 28, 2026.
Abstract
Antigen presentation by major histocompatibility complex class I (MHC-I) is critical for tumor cell killing by CD8+ T cells. In human papillomavirus-positive head and neck cancer (HPV+ HNC), where MHC-I downregulation is frequent despite favorable immune cell infiltration, lower MHC-I levels are associated with poor responses to immune checkpoint inhibitor therapy. However, the mechanism of MHC-I degradation remains elusive. Genome-wide CRISPR screens in HPV+ HNC identified components of the ULK1 and PIK3C3 autophagy initiation complexes among top negative regulators of cell-surface MHC-I. In contrast, inhibiting post-initiation stages of autophagy did not restore cell-surface MHC-I, highlighting a critical role for autophagy initiation in regulation of MHC-I. Mechanistically, we showed that MHC-I is recruited from the ER to autophagosomes by the cargo receptor NDP52. Finally, inhibition of autophagy initiation suppressed HPV+ HNC tumor growth in vivo and enhanced the CD8+ T cell-mediated antitumor response. Our findings suggest that autophagic degradation of MARCHF8-ubiquitinated MHC-I is a key immune evasion mechanism in HPV+ HNC.
PMID:
42803943
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.
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