Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment.

Targeted immunotherapy has improved patient survival in head and neck squamous cell carcinoma (HNSCC), but less than 20% of patients produce a durable response to these treatments. Thus, new immunotherapies that consider all key players of the complex HNSCC tumour microenvironment (TME) are necessary to further enhance tumour-specific T cell responses in patients. HNSCC is an ideal tumour type in which to evaluate immune and non-immune cell differences because of two distinct TME aetiologies (human papillomavirus (HPV)-positive and HPV-negative disease), multiple anatomic sites for tumour growth, and clear distinctions between patients with locally advanced disease and those with recurrent and/or metastatic disease. Recent technological and scientific advancements have provided a more complete picture of all cellular constituents within this complex TME and have evaluated the interplay of both immune and non-immune cells within HNSCC. Here, we include a comprehensive analysis of the complete ecosystem of the HNSCC TME, performed utilizing data-rich resources such as The Cancer Genome Atlas, and cutting-edge techniques, such as single-cell RNA sequencing, high-dimensional flow cytometry and spatial multispectral imaging, to generate improved treatment strategies for this diverse disease.

Impact of exercise on oocyte quality in the POLG mitochondrial DNA mutator mouse.

The mtDNA 'mutator' mouse, also called the 'POLG' mouse, is a well-characterized model frequently used for studies of progeroid aging. Harboring a mutation in the proofreading domain of the mitochondrial polymerase, polymerase-γ (Polg), POLG mice acquire mtDNA mutations at an accelerated rate. This results in premature mitochondrial dysfunction and a systemic aging phenotype. Previous work has demonstrated that the progeroid phenotype in POLG is attenuated following endurance exercise, the only reported intervention to extend health span and lifespan of these mice. Herein, oocyte quality was evaluated in sedentary and exercised POLG mice. In mice homozygous for the Polg mutation, litter size is dramatically reduced as compared to heterozygous Polg mice. Following ovarian hyper-stimulation, oocytes were retrieved until 9 months of age in exercised and sedentary groups, with no oocytes ovulated thereafter. Although ovulated oocyte numbers were not impacted by exercise, we did find a modest improvement in both the ovarian follicle reserve and in oocyte quality based on meiotic spindle assembly, chromosomal segregation and mitochondrial distribution at 7 months of age in exercised POLG mice as compared to sedentary counterparts. Of note, analysis of mtDNA mutational load revealed no differences between exercised and sedentary groups. Collectively, these data indicate that exercise differentially influences somatic tissues of the POLG mouse as compared to oocytes, highlighting important mechanistic differences between mitochondrial regulatory mechanisms in the soma and the germline.