ULK1-dependent autophagy initiation promotes MHC-I degradation and immune evasion in HPV-positive head and neck cancer

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.