title: Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions.
abstract: OBJECTIVE
  The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non-small cell lung tumors.
  
  
  METHODS
  Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21-day (>1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors.
  
  
  RESULTS
  We found that the high-dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8(+) T-cell tumor infiltrate, and a loss of myeloid-derived suppressor cells (MDSC). The change was dependent on antigen cross-presenting CD8(+) dendritic cells, secretion of IFNγ, and CD4(+)T cells expressing CD40L. Antitumor CD8(+) T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated durable remissions in an IFNγ-dependent manner. Interestingly, extended fractionated radiation regimen did not result in robust CD8(+) T-cell infiltration.
  
  
  CONCLUSIONS
  For immunologically sensitive tumors, these results indicate that remissions induced by a short course of high-dose radiotherapy depend on the development of antitumor immunity that is reflected by the nature and kinetics of changes induced in the tumor cell microenvironment. These results suggest that systematic examination of the tumor immune microenvironment may help in optimizing the radiation regimen used to treat tumors by adding a robust immune response.
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California. sstrober@stanford.edu afilaten@standord.edu.
authors: Alexander
authors: A
authors: Filatenkov
authors: Division of Blood and Bone Marrow Transplantation, Department of Medicine, Stanford University, School of Medicine, Stanford, California.
authors: Jeanette
authors: J
authors: Baker
authors: Division of Blood and Bone Marrow Transplantation, Department of Medicine, Stanford University, School of Medicine, Stanford, California.
authors: Antonia M S
authors: AM
authors: Mueller
authors: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors: Justin
authors: J
authors: Kenkel
authors: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors: G-One
authors: GO
authors: Ahn
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Suparna
authors: S
authors: Dutt
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Nigel
authors: N
authors: Zhang
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Holbrook
authors: H
authors: Kohrt
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Kent
authors: K
authors: Jensen
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Sussan
authors: S
authors: Dejbakhsh-Jones
authors: Division of Blood and Bone Marrow Transplantation, Department of Medicine, Stanford University, School of Medicine, Stanford, California.
authors: Judith A
authors: JA
authors: Shizuru
authors: Division of Blood and Bone Marrow Transplantation, Department of Medicine, Stanford University, School of Medicine, Stanford, California.
authors: Robert N
authors: RN
authors: Negrin
authors: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors: Edgar G
authors: EG
authors: Engleman
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California. sstrober@stanford.edu afilaten@standord.edu.
authors: Samuel
authors: S
authors: Strober
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D003713:Dendritic Cells / Q000276:immunology / Q000528:radiation effects; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000528:radiation effects; D012074:Remission Induction; D059016:Tumor Microenvironment / Q000276:immunology* / Q000528:radiation effects