Journal Article

Protein translation dysregulation and immune cell evasion mediated by IFN and immunoproteasome downregulation define metastatic clones in HPV-related cancer of the oropharynx

Keith, Patricia, McCloy, Rachael A., Spenceley, Eleanor, Chin, Venessa T., Neavin, Drew R., Powell, Joseph E., Leavers, Brett, Sudhakar, Kavitha Krishna, Gallagher, Richard, Kaczorowski, Dominik, Floros, Peter, Arora, Himanshi, Muskovic, Walter, Alquicira-Hernandez, Jose, Crawford, Julia A., Senabouth, Anne

2025

Overview

Background Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is increasing in prevalence, but the drivers of metastasis remain poorly understood, which impacts the ability to personalise management decisions. Much of the genomic research to date focuses on the HPV-negative population. Here, we utilise single-cell and spatial single-cell techniques to understand the drivers of metastasis. Methods Patients with HPV-positive OPC and cervical lymph node metastases treated with curative surgery had matched samples from the primary and lymph nodes collected for research. Single-cell RNA sequencing, single-cell spatial sequencing (Visium) and in-situ spatial platforms were performed. Cancer clones were delineated using inferred copy number variation. Expression phenotypes and interactions with the tumour microenvironment were compared between the metastasising and non-metastasising cancer clones. Results Individual cancer clones have varied abilities to metastasise and undergo clonal expansion in the lymph node, with only a subset of clones present in the primary expanding in the lymph node. Four mechanisms were identified as defining the metastatic phenotype, including protein translation adaptation, immunoproteasome dysfunction and immune evasion, suppression of the IFN immune response and cap-independent protein translation. Conclusions This research elucidates multiple mechanisms driving the expansion of cancer clones in HPV-positive oropharyngeal cancer. By detailing the roles of translational adaptation, immunoproteasome dysfunction, suppression of the interferon immune response and cap-independent protein translation, we provide insights into how these processes contribute to immune evasion and tumour survival.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Adaptation / Aged / Apoptosis / Biomarkers / Biomedicine / Cancer / Cancer therapies / Care and treatment / Cell cycle / Cloning / Complications and side effects / Copy number / Deoxyribonucleic acid / Development and progression / DNA / Down-Regulation / Ethylenediaminetetraacetic acid / Female / Gene expression / Gene sequencing / Genetic aspects / Genetic translation / Genomics / Geospatial data / Health aspects / Human papillomavirus / Humans / Immune Evasion / Immune response / Immune system / Interferon / Interferons - immunology / Interferons - metabolism / Lymph nodes / Lymphatic Metastasis / Lymphatic system / Male / Medical prognosis / Medicine / Medicine & Public Health / Metastases / Metastasis / Middle Aged / Oncology, Experimental / Oropharyngeal cancer / Oropharyngeal Neoplasms - genetics / Oropharyngeal Neoplasms - immunology / Oropharyngeal Neoplasms - pathology / Oropharyngeal Neoplasms - virology / Oropharynx / Papillomaviridae / Papillomavirus infections / Papillomavirus Infections - complications / Papillomavirus Infections - immunology / Patients / Phenotypes / Phenotypic variations / Proteasome Endopeptidase Complex - genetics / Proteasome Endopeptidase Complex - metabolism / Protein Biosynthesis / Proteins / Ribonucleic acid / RNA / RNA sequencing / Single-Cell Analysis / Software / Throat cancer / Translation / Tumor Microenvironment / Tumors / Ubiquitin-proteasome system / Viral infections