Using samples from cetuximab + radiochemotherapy-treated clinical trial patients with pancreatic cancer, Walle et al. showed that NK cells egressed from peripheral blood, and CXCL8 (IL-8) levels increased in serum; both correlated with patient survival. Radiotherapy (RT) induced CXCR1/2+CD56dim NK cell accumulation in resected tumors from an independent cohort, and NF-kB/mTOR regulated CXCL8 release from senescing tumor cells in vitro. In a mouse xenograft model, RT induced human NK cell infiltration toward, and CXCL8 release from human tumor cells. Combining adoptive human NK cell transfer with RT enhanced antitumor activity.
Contributed by Paula Hochman
ABSTRACT: Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56dim-like cytotoxic transcriptomic states. In experimental models, NF-κB and mTOR orchestrated radiation-induced CXCL8 secretion from tumor cells with senescence features causing directional migration of CD56dim NK cells, thus linking senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined high-dose radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice, suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy.
Author Info: (1) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Medical Oncology, National Center for Tumor Diseases (NCT),
Author Info: (1) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. Department of Immunobiochemistry and MI3, Mannheim Institute for Innate Immunoscience, Heidelberg University, Medical Faculty Mannheim, Mannheim, Germany. (2) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiooncology and Radiotherapy, University Hospital Heidelberg, Heidelberg, Germany. (3) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiooncology and Radiotherapy, University Hospital Heidelberg, Heidelberg, Germany. (4) Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, Heidelberg, Germany. Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany. (5) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiation Oncology, St. Franziskus Hospital, Flensburg, Germany. (6) Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, Heidelberg, Germany. Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany. (7) Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany. (8) Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. (9) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (10) Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, Heidelberg, Germany. Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany. (11) Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, Heidelberg, Germany. Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany. (12) Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiooncology and Radiotherapy, University Hospital Heidelberg, Heidelberg, Germany. (14) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (15) Leibniz Institute for Immunotherapy, Division of Interventional Immunology, Regensburg, Germany. (16) Core Facility Light Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany. (17) Core Facility Light Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany. (18) Department of Immunobiochemistry and MI3, Mannheim Institute for Innate Immunoscience, Heidelberg University, Medical Faculty Mannheim, Mannheim, Germany. (19) Institute of Pathology University Hospital Heidelberg, Heidelberg, Germany. (20) Department of Immunobiochemistry and MI3, Mannheim Institute for Innate Immunoscience, Heidelberg University, Medical Faculty Mannheim, Mannheim, Germany. (21) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiooncology and Radiotherapy, University Hospital Heidelberg, Heidelberg, Germany. (22) Core Facility Light Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany. (23) Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. (24) Leibniz Institute for Immunotherapy, Division of Interventional Immunology, Regensburg, Germany. (25) Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany. (26) Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, Heidelberg, Germany. (27) Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. (28) Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (29) Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany. Helmholtz Center for Translational Oncology (HITRON), Mainz, Germany. Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany. (30) Department of Radiooncology and Radiotherapy, University Hospital Heidelberg, Heidelberg, Germany. Heidelberg Ion Therapy Center (HIT), Heidelberg, Germany. Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany. (31) Department of Immunobiochemistry and MI3, Mannheim Institute for Innate Immunoscience, Heidelberg University, Medical Faculty Mannheim, Mannheim, Germany. (32) Department of Molecular and Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiooncology and Radiotherapy, University Hospital Heidelberg, Heidelberg, Germany. Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany.
