Radiotherapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here, we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance. Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine head and neck squamous cell carcinoma (HNSCC) tumors using mass cytometry and whole-genome sequencing. Mice were treated with anti-PD-L1 or anti-TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T-cell populations. Depletion of regulatory T cells (Treg) was performed using anti-CD25 antibody. We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti-TIM-3 concurrently with anti-PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC. Despite this treatment combination, the response was not durable, and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored antitumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory. These data reveal multiple layers of immune regulation that can promote tumorigenesis and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. .

Objective. Opioid use and abuse is a national health care crisis, yet opioids remain the cornerstone of pain management in cancer. We sought to determine the risk of acute and chronic opioid use with head and neck squamous cell cancer (HNSCC) treatment. Study Design. Retrospective population-based study. Setting. Surveillance, Epidemiology and End Results (SEER)-Medicare database from 2008 to 2011. Subjects and Methods. In total, 976 nondistant metastatic oral cavity and oropharynx patients undergoing cancer-directed treatment enrolled in Medicare were included. Opiate use was the primary end point. Univariate and multivariable logistic analyses were completed to determine risk factors. Results. Of the patients, 811 (83.1%) received an opioid prescription during the treatment period, and 150 patients (15.4%) had continued opioid prescriptions at 3 months and 68 (7.0%) at 6 months. Opioid use during treatment was associated with prescriptions prior to treatment (odds ratio [OR], 3.28; 95% confidence interval [CI], 2.11–5.12) and was least likely to be associated with radiation treatment alone (OR, 0.35; 95% CI, 0.18–0.68). Risk factors for continued opioid use at both 3 and 6 months included tobacco use (OR, 2.23; 95% CI, 1.05–4.71 and OR, 3.84; 95% CI, 1.44–10.24) and opioids prescribed prior to treatment (OR, 3.84; 95% CI, 2.45–5.91 and OR, 3.56; 95% CI, 1.95–6.50). Oxycodone prescribed as the first opioid was the least likely to lead to ongoing use at 3 and 6 months (OR, 0.33; 95% CI, 0.17–0.62 and OR, 0.26; 95% CI, 0.10–0.67). Conclusion. Patients with oral/oropharyngeal cancer are at a very high risk for receiving opioids as part of symptom management during treatment, and a significant portion continues use at 3 and 6 months after treatment completion.

IMPORTANCE Oral cavity squamous cell carcinoma (OCSCC) is associated with often-delayed clinical diagnosis, poor prognosis, and expensive therapeutic approaches. Prognostic accuracy is important in improving treatment outcomes of patients with this disease.OBJECTIVES To assess lymph node ratio (LNR) and other factors in estimating response to treatment and provide prognostic information helpful for clinical decision making.

Objectives: Studies have shown the utility of lipid-lowering agents in improving outcomes in various cancers. We aim to explore how statins affect overall survival and cancer specific survival in head and neck cancer patients using population-based datasets. Patients and methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked dataset, we separated HNC patients into three groups: those with no hyperlipidemia (nH), those with hyperlipidemia and not taking a statin (HnS), and those with hyperlipidemia and taking a statin (H + S). Overall survival (OS) and cancer specific survival (CSS) were compared between the three groups based on disease subsite (oral cavity, oropharynx, and other) using Kaplan-Meier and multivariate Cox regression analysis (MVA), controlling for demographic, socioeconomic, staging, treatment, and comorbidity covariates. Using Pearson chi-square analysis, we also compared the incidence of cancer-related toxicity events. Results: There were 495 nH, 567 HnS, and 530 H + S patients. H + S patients had superior OS and CSS (73.0, 81.2%) relative to nH (58.6, 69.1%) and HnS groups (61.7, 69.2%) (p < 0.01). On MVA, H + S patients showed improved OS (p < 0.01) and CSS (p = 0.04) compared to nH (HR = 1.64, 1.56) and HnS (HR = 1.40, 1.37). MVA stratified by subsite yielded similar results for oral cavity and oropharyngeal disease. Toxicity-related events did not differ significantly between the groups. Conclusion: HNC patients with hyperlipidemia and taking a statin demonstrated improved outcomes compared to nH and HnS patients, further supporting statins’ role as a potential adjuvant anti-neoplastic agent in HNC. Further prospective studies to investigate the impact of statins on HNC outcomes are warranted.