Age-associated alterations in head and neck cancer
Embargo Date
2027-02-06
OA Version
Citation
Abstract
Head and neck squamous cell carcinomas (HNSCC) are the seventh most common cancers globally and have poor survival rates. Current first-line treatments for HNSCC, which include surgical resection and radiotherapy, result in high post-treatment morbidity while alternative treatment modalities, such as broad-based chemotherapy and immunotherapy, have limited long term efficacy. Thus, there is a need to identify novel factors that mediate the etiology of HNSCC to improve clinical outcomes for patients. One such modulating factor may be aging. The median age of diagnosis for HNSCC is above the age of 65, and older age is associated with increased incidence, reduced survival, and limited treatment efficacy for HNSCC patients. Aging is associated with a multitude of cellular, molecular, and genomic processes that alter the function of tissues, including tumors, such as cellular senescence, reduced immune functions, and altered stromal composition. Despite these tissue modifying features and the largely elderly HNSCC patient population, most pre-clinical cancer models are comprised exclusively of young animals, a discrepancy that likely contributes to the limited efficacy of pharmacological treatments for HNSCC. In these studies, we used carcinogen-induced and syngeneic isograft models of HNSCC orthotopically implanted into the tongues of young (≤16 weeks old; equivalent to approximately a 20-30 year old in human age) and old ((≥75 weeks old; equivalent to approximately a 60-80 year old in human age) mice to elucidate the role of the aged oral tumor microenvironment in modulating oral tumor biology. We observed that older age promotes malignant features in oral lesions. Additionally, we identified an enrichment of an age-associated, immune-evasive carcinoma cell population that coincided with reduced immune infiltration in tumors in old mice, molecular features that corresponded to reduced immune infiltration in human HNSCC. We further identified an age-associated, pro-fibrotic fibroblast population in the aged oral microenvironment that corresponded to elevated collagen deposition and elevated yes-associated protein (YAP) and TEA-domain transcription factor family (TEAD) activity in oral carcinoma cells in old mice. We demonstrated that targeting YAP-TEAD activity restored the immunogenicity of oral carcinoma cells, enhancing immune infiltration and tumor clearance in old mice. In additional studies, we demonstrated that supplementing absent chemokines into the old oral tumor microenvironment can also restore intra-tumoral immune infiltration to promote tumor clearance. Furthermore, we demonstrated that the induction of an age-associated, fibrotic stroma in young mice can partially recapitulate both the growth dynamics and immune-evasive phenotypes in oral carcinoma cells observed in old mice. Overall, these studies highlight the critical importance that aging plays in directing tumor biology in HNSCC, that YAP-TEAD contribute to mediating these dynamics, and that targeting age-associated alterations in the carcinoma cell, immune, or stromal compartments could serve as viable avenues for therapeutic intervention to improve outcomes for older HNSCC patients.
Description
2027
License
Attribution 4.0 International