Chronic Phenotypes Underlying Radiation-Induced Salivary Gland Dysfunction

Abstract

Head and neck cancer (HNC) is the sixth most diagnosed cancer, and treatment typically consists of surgical removal of the tumor followed by ionizing radiation (IR). While excellent at controlling tumor growth, IR often damages salivary glands due to their proximity to common tumor sites. Radiation damage to salivary glands results in loss of secretory function, causing severe and chronic reductions in salivary flow. This leads to the patient-reported sensation of dry mouth, termed xerostomia, which significantly reduces quality of life for HNC patients and survivors. The mechanisms underlying salivary gland damage remain elusive, and therefore, treatment options are scarce. Available therapies provide temporary symptom relief, but there is no standard of care for permanent restoration of function. There is a significant gap in understanding the chronic mechanistic responses to radiation as well as treatments that can be given in the months to years following cessation of treatment. HNC cases are steadily rising; particularly, the number of young patients diagnosed with nonfatal human papillomavirus + HNC continues to increase. The growing number of HNC diagnoses and improved prognoses results in more people living with xerostomia, which highlights the mounting need for restorative treatments. Mechanisms underlying chronic damage include decreases in acinar differentiation markers, increases in acinar cell proliferation, immune and inflammatory dysregulation, and metabolic changes including increases in amino acids and reductions in glycolysis and oxidative phosphorylation, fibrosis, and dysregulated neuronal responses. Currently, promising treatment options include adenoviral gene transfers and stem cell therapy. Thus, this review describes in depth known mechanisms contributing to chronic damage and discusses therapeutic advances in treating chronically damaged glands. Understanding the chronic response to radiation offers potential in development of new therapeutics to reverse salivary gland damage and improve the quality of life of HNC survivors.

Keywords: head and neck cancer; parotid glands; quality of life; salivary glands; submandibular glands; xerostomia.

Figure.

Timeline of phenotypes influencing the chronic radiation damage response. Following ionizing radiation (IR) therapy, animal models show a reduction in salivary flow beginning at day 3 that persists through chronic time points (Jasmer et al. 2020). Increases in proliferation markers and reductions in differentiation are observed through day 90, while a loss of apical basolateral polarity is observed through day 30 (Chibly et al. 2018; Emmerson et al. 2018; Wong et al. 2019; Lombaert et al. 2020). Changes in the immune and inflammatory response, including increases in double positive T cells and neutrophils and changes in proinflammatory cytokines, are observed at day 30, and the increase in double-positive T cells is seen through 10 mo, as measured by scRNAseq (Hu et al. 2021; Rheinheimer et al. 2023; Gunning et al. 2024). Both increases and decreases in macrophages have been reported around 1 mo following IR (Hu et al. 2021; Gunning et al. 2024). Reductions in glycolytic flux and oxidative phosphorylation (OXPHOS) have been reported at 30 and 60 d after IR, and increases in amino acids have been observed at 30 d after IR (Meeks et al. 2021; Buss et al. 2024). Fibrosis is generally reported 4 to 6 mo following IR but has been observed as soon as 8 wk post-IR and is often associated with increases in transforming growth factor–β (Lombaert et al. 2020). Increases in cellular senescence markers and reductions in anti-senescence cytokines have been observed at 5 wk post-IR in animal models and after 4 mo in clinical studies (Marmary et al. 2016; Hu et al. 2021). Data from clinical studies illustrate neuronal changes, including reduced parasympathetic innervation and dysregulation of neurotrophin signaling, begin around 4 mo and persist for years following IR (Emmerson et al. 2018; Chibly et al. 2023).