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Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients.

enhance recovery after surgery or trauma. It has also been reported to have beneficial effects on glycaemic control in diabetic patients, while rodent studies suggest that it may reduce body weight and lessen hyperglycaemia. Objective: The present study aimed to investigate the effects of daily supplementation of glutamine to high fat diet and to assess this in a mouse model with abnormal feeding behaviour: the Snord116 knockout mouse. Research methods: Adult male C57BL/6 mice and mice with deletion of the Snord116 gene cluster (implicated in Prader-Willi syndrome) were given ad libitum access to HFD for 12 weeks. Mice of both genotypes were randomly assigned to either the treatment or non-treatment group. Animals were supplemented with glutamine in food (40 mg/g HFD). Body weight was monitored weekly. Spontaneous and fasting-induced food intake, glucose tolerance and insulin sensitivity, energy expenditure and body composition were assessed between 14 and 18 weeks of age. Results: Glutamine treatment did not attenuate the development of HFD-induced obesity in either WT or Snord116 knockout mice, with treatment and non-treatment groups within genotypes gaining weight at a similar rate during the monitoring period. There was also no difference between treatment groups within genotypes in food intake, glucose tolerance, insulin tolerance, energy expenditure or adiposity. Conclusion: Our results did not find evidence that would support beneficial metabolic effects of glutamine when administered daily; either in WT or Snord116 knockout mice fed a HFD.

Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans. Recent clinical reports have suggested that micro-deletion of the Snord116 gene cluster can lead to PWS, however, the extent of the contributions of the encoded snoRNAs is unknown. Here we show that mice lacking Snord116 globally have low birth weight, increased body weight gain, energy expenditure and hyperphagia. Consistent with this, microarray analysis of hypothalamic gene expression revealed a significant alteration in feeding related pathways that was also confirmed by in situ hybridisation. Importantly, selective deletion of Snord116 only from NPY expressing neurons mimics almost exactly the global deletion phenotype including the persistent low birth weight, increased body weight gain in early adulthood, increased energy expenditure and hyperphagia. Mechanistically, the lack of Snord116 in NPY neurons leads to the upregulation of NPY mRNA consistent with the hyperphagic phenotype and suggests a critical role of Snord116 in the control of NPY neuronal functions that might be dysregulated in PWS.