Immune receptor degradation for immune evasion of head and neck cancer

PROJECT SUMMARY Human papillomaviruses (HPVs) cause 5% of all human cancers, including most cervical cancers and approximately 25% of head and neck squamous cell carcinomas (HNSCCs). The alarming rise in cases of HPV- positive (HPV+) HNSCCs has been observed over the past few decades. Despite this, our understanding of the precise mechanisms underlying HPV-driven disease progression, particularly concerning the host immune response, remains limited. Current immunotherapies with immune checkpoint inhibitors (ICIs) reactivate exhausted T cells. However, in cancers like HPV+ HNSCC, downregulation of major histocompatibility complex class I (MHCI) and costimulatory molecules hampers T-cell responses. The mechanisms behind this downregulation are largely unknown. HPV+ HNSCC patients consistently show low MHCI and costimulatory receptors on tumor cells, contributing to poor response rates in ICI therapy. Membrane-associated RING-CH finger 8 (MARCHF8), homologous to Kaposi’s sarcoma herpesvirus K3 and K5, downregulates MHCI through ubiquitination. Our study revealed that HPV activates MARCHF8, promoting MHCI degradation. Knocking out MARCHF8 in HPV+ HNSCC cells increased the expression of multiple immune receptors, including MHCI, improved mouse survival, and enhanced NK and T cell infiltration. Notably, we also identified that the MARCHF8-mediated ubiquitination of MHCI triggers its degradation via selective autophagy. Based on these compelling results, we propose that the MARCHF8- autophagy axis plays a crucial role in promoting cancer progression by evading T-cell responses. This indicates that targeting the MARCHF8-autophagy pathway could offer a promising therapeutic strategy for novel immunotherapies to treat HPV+ HNSCC. In this project, we will 1) determine if targeting MARCHF8 activates antitumor immunity by remodeling the tumor microenvironment of HPV+ HNSCC; 2) determine the mechanisms by which MARCHF8 ubiquitinates and degrades MHCI proteins; and 3) develop novel immunotherapies by targeting the MARCHF8-autophagy pathway. Current immunotherapies using ICIs have limited success, with over 70% of patients not responding. ICI- refractory cancers show low MHCI expression and T-cell infiltration. Targeting MARCHF8 and autophagy could restore immune receptors and offer new treatment options for non-responders with HNSCC.