ABSTRACT
BACKGROUND: γ-radiation is an effective treatment for cancer. There is evidence that radiotherapy supports tumor-specific immunity. It was described that irradiation induces de novo protein synthesis and enhances antigen presentation, we therefore investigated whether γ-radiation results in increased expression of cancer-testis (CT) antigens and MHC-I, thus allowing efficient immunological control. This is relevant because the expression of CT-antigens and MHC-I on tumor cells is often heterogeneous. We found that the changes induced by γ-radiation promote the immunological recognition of the tumor, which is illustrated by the increased infiltration by lymphocytes after radiotherapy. METHODS/FINDINGS: We compared the expression of CT-antigens and MHC-I in various cancer cell lines and fresh biopsies before and after in vitro irradiation (20 Gy). Furthermore, we compared paired biopsies that were taken before and after radiotherapy from sarcoma patients. To investigate whether the changed expression of CT-antigens and MHC-I is specific for γ-radiation or is part of a generalized stress response, we analyzed the effect of hypoxia, hyperthermia and genotoxic stress on the expression of CT-antigens and MHC-I. In vitro irradiation of cancer cell lines and of fresh tumor biopsies induced a higher or de novo expression of different CT-antigens and a higher expression of MHC-I in a time- and dose-dependent fashion. Importantly, we show that irradiation of cancer cells enhances their recognition by tumor-specific CD8+ T cells. The analysis of paired biopsies taken from a cohort of sarcoma patients before and after radiotherapy confirmed our findings and, in addition showed that irradiation resulted in higher infiltration by lymphocytes. Other forms of stress did not have an impact on the expression of CT-antigens or MHC-I. CONCLUSIONS: Our findings suggest that γ-radiation promotes the immunological recognition of the tumor. We therefore propose that combining radiotherapy with treatments that support tumor specific immunity may result in increased therapeutic efficacy.
Subject(s)
Antigens, Neoplasm/metabolism , Gamma Rays , Neoplasms/immunology , Antigens, Neoplasm/genetics , Ataxia Telangiectasia Mutated Proteins , Biopsy , Cell Cycle Proteins/metabolism , Cell Line, Tumor , DNA-Activated Protein Kinase/metabolism , DNA-Binding Proteins/metabolism , Female , Gene Expression Regulation, Neoplastic/radiation effects , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/metabolism , Humans , Lymphocytes, Tumor-Infiltrating/radiation effects , Male , Neoplasms/genetics , Neoplasms/pathology , Nuclear Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/radiation effects , Stress, Physiological/radiation effects , T-Lymphocytes/immunology , T-Lymphocytes/radiation effects , Tumor Suppressor Proteins/metabolism , Up-Regulation/radiation effectsABSTRACT
Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases of animals and humans. Many TSEs are initiated by prion replication in the lymphoreticular system (LRS). The cellular and molecular prerequisites for prion trafficking within the LRS are not fully understood. Here we have manipulated CD40 and its ligand to investigate whether genetic or pharmacological ablation of germinal center B cells (GCBs), which migrate into and out of germinal centers, influences prion pathogenesis. In contrast to previous reports, no alteration of prion pathogenesis was detected in mice lacking CD40L and in mice treated with anti-CD40L antibodies. These results suggest that GCBs alone do not impact peripheral splenic prion transport, replication efficiency, or neuroinvasion, and point to other mechanisms affecting prion transport from lymphoreticular sites of replication to the nervous system.
