Head and neck squamous cell carcinoma (HNSCC) is a unique malignancy associated with two distinct risk factors: exposure to typical carcinogens and infection of human papillomavirus (HPV). HPV encodes the potent oncoproteins E6 and E7, which bypass many important oncogenic processes and result in cancer development. In contrast, HPV-negative HNSCC is developed through multiple mutations in diverse oncogenic driver genes. While the risk factors associated with HPV-positive and HPV-negative HNSCCs are discrete, HNSCC patients still show highly complex molecular signatures, immune infiltrations, and treatment responses even within the same anatomical subtypes. Here, we summarize the current understanding of biological mechanisms, treatment approaches, and clinical outcomes in comparison between HPV-positive and -negative HNSCCs.

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.

Antigen presentation by MHC class I (MHC-I) is critical for tumor cell killing by CD8+ T cells. In human papillomavirus–positive head and neck cancer (HPV+ HNC), in which 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 postinitiation 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 endoplasmic reticulum 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.