Herrera et al. demonstrated that low-dose radiotherapy (LDRT) can be used on immune-cold metastatic tumors in high volumes without toxicity, and reprograms the TME to promote immune cell infiltration and responses to immunotherapy. LDRT sensitized tumors to a rationally designed immunotherapy combination in a CD4+ and CD8+ T cell-dependent manner, expanded T cells with progenitor exhausted and exhausted features (with a subset expressing NKG2D), and mobilized activated dendritic cells expressing the NKG2D ligand Rae1. In phase I clinical trial, combinatorial treatment regressed metastatic solid tumors and increased T cell influx in responding patients.
Contributed by Shishir Pant
ABSTRACT: Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand Rae1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide and immune checkpoint blockade to patients with immune desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low-T cell infiltrated tumors.
Author Info: (1) Oncology at Lausanne University Hospital, Ludwig Institute for Cancer Research and Immuno-Oncology and Radiation Oncology Services. (2) Department of Oncology, Ludwig Institute
Author Info: (1) Oncology at Lausanne University Hospital, Ludwig Institute for Cancer Research and Immuno-Oncology and Radiation Oncology Services. (2) Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne. (3) Medical Oncology Department, Centre Hospitalier Universitaire Vaudois. (4) Oncology, Centre hospitalier universitaire vaudois. (5) Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne. (6) Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne. (7) Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne. (8) Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne. (9) Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne. (10) Department of Oncology, University of Lausanne. (11) Oncology, Lausanne University Hospital (CHUV). (12) Oncology, Lausanne University Hospital (CHUV). (13) DOF, Ludwig Institute for Cancer Research, and Department of Oncology, University of Lausanne. (14) Oncology, University Hospital Center and University of Lausanne, Ludwig Cancer Research Institute. (15) Department of Oncology, Lausanne University Hospital. (16) Oncology, Lausanne University Hospital (CHUV). (17) Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois. (18) Radiology and Interventional Radiology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne. (19) Department of Radiology; CHUV University Hospital, Lausanne, Switzerland, Department of Radiology; CHUV University Hospital, Lausanne, Switzerland. (20) Nuclear Medicine and Molecular Imaging, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne. (21) Department of Medical Oncology; CHUV University Hospital, Lausanne, Switzerland. (22) Department of Radio-Oncology, Centre Hospitalier Universitaire Vaudois (CHUV). (23) Statistics, Scientific Research Consulting Hellas, Statistics Center, Athens, Greece. (24) School of Nursing, National and Kapodistrian University of Athens. (25) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School. (26) NanoString Technologies Inc. (27) Research and Development, NanoString Technologies, Inc. (28) Oncology, CHUV Lausanne. (29) Center of Experimental Therapeutic, CHUV. (30) Pathology and Immunology, University of Geneva. (31) Oncology, Lausanne University Hospital (CHUV). (32) Institute of Pathology, CHUV, University of Lausanne. (33) Laboratory of Biostatistics, National and Kapodistrian University of Athens and Frontier Science Foundation-Hellas. (34) Oncology, University Hospital of Lausanne. (35) Oncology, CHUV, UNIL, Ludwig Institute for Cancer Research. (36) Department of Oncology, University of Lausanne. (37) Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research and Department of Oncology, Lausanne University Hospital (CHUV). (38) Ludwig Cancer Research, Department of Oncology, University of Lausanne. (39) Department of Oncology, LICR, DOF, CHUV George.Coukos@chuv.ch.
