The membrane-associated ubiquitin ligase MARCHF8 promotes cancer immune evasion by degrading MHC class I proteins

The current immunotherapy is effective, but many cancer patients do not respond. The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed as a mechanism by which cancer cells evade tumor-specific T cells in Immune Checkpoint Inhibitor (ICI)-refractory patients. Nevertheless, how cancer cells downregulate MHC-I 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 proteins in HPV-positive head and neck cancer (HPV+ HNC). MARCHF8 knockdown restores MHC-I levels on HPV+ HNC cells. We further reveal that Marchf8 knockout significantly suppresses tumor growth and increases the infiltration of natural killer (NK) and T cells in the tumor microenvironment (TME). Furthermore, Marchf8 knockout markedly increases the cytotoxic NK cells and CD8+ T cells and their crosstalk with macrophages and enhances the tumor cell-killing activity of CD8+ T cells. CD8+ T cell depletion in mice abrogates Marchf8 knockout-driven tumor suppression and NK and T cell infiltration. Interestingly, Marchf8 knockout, in combination with anti-PD-1 treatment, synergistically suppresses tumor growth in mice bearing ICI-refractory tumors. Taken together, our finding suggests that MARCHF8 could be a promising target for novel immunotherapy for HPV+ HNC patients.