Induction or selection of radioresistant cancer (stem) cells following standard radiotherapy is presumably one of the major causes for recurrence of metastatic disease. One possibility to prevent tumor relapse is the application of targeted immunotherapies including, e.g., chimeric antigen receptor (CAR) T cells. In light of long-term remissions, it is highly relevant to clarify whether radioresistant cancer cells are susceptible to CAR T cell-mediated killing. To answer this question, we evaluated the anti-tumor activity of the switchable universal chimeric antigen receptor (UniCAR) system against highly radioresistant head and neck squamous cell carcinoma cells both in vitro and in vivo. Following specific UniCAR T cell engagement via EGFR or CD98 target modules, T cell effector mechanisms were induced including secretion of pro-inflammatory cytokines, up-regulation of granzyme B and perforin, as well as T cell proliferation. CD98- or EGFR-redirected UniCAR T cells further possess the capability to efficiently lyse radioresistant tumor cells. Observed anti-tumor effects were comparable to those against the radiosensitive parental cell lines. Finally, redirected UniCAR T cells significantly inhibited the growth of radioresistant cancer cells in immunodeficient mice. Taken together, our obtained data underline that the UniCAR system is able to overcome radioresistance. Thus, it represents an attractive technology for the development of combined radioimmunotherapeutic approaches that might improve the outcome of patients with metastatic radioresistant tumor diseases.

CROmed Translational Research Centers Budapest Hungary

Department of Neurology Center of Clinical Neuroscience University Hospital Carl Gustav Carus TU Dresden Dresden Germany

Department of Radioimmunology Helmholtz Zentrum Dresden Rossendorf Institute of Radiopharmaceutical Cancer Research Dresden Germany

Department of Radiotherapy and Radiation Oncology Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

German Cancer Consortium Heidelberg Germany

Helmholtz Zentrum Dresden Rossendorf Institute of Radiooncology OncoRay Dresden Germany

Institute of Immunology Faculty of Medicine Carl Gustav Carus TU Dresden Dresden Germany

Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic Prague Czech Republic

Medical Clinic and Polyclinic 1 University Hospital Carl Gustav Carus TU Dresden Dresden Germany

Monash Biomedical Imaging School of Psychological Sciences and Australian Research Council Centre of Excellence for Integrative Brain Function Monash University Melbourne Australia

National Center for Tumor Diseases Dresden Germany

OncoRay National Center for Radiation Research in Oncology Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden Helmholtz Zentrum Dresden Rossendorf Dresden Germany

Semmelweis University Department of Biophysics and Radiation Biology Budapest Hungary

UniversityCancerCenter Tumor Immunology University Hospital Carl Gustav Carus TU Dresden Dresden Germany

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