title: Tumor Eradication by Cisplatin Is Sustained by CD80/86-Mediated Costimulation of CD8+ T Cells.
abstract: Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that are not completely understood. Here we show how the DNA-damaging drug cisplatin modulates tumor immunity. At the maximum tolerated dose (MTD), cisplatin cured 50% of mice with established murine TC-1 or C3 tumors, which are preclinical models of human papillomavirus (HPV)-associated cancer. Notably, the curative benefit of cisplatin relied entirely upon induction of tumor-specific CD8+T cells. Mechanistic investigations showed that cisplatin stimulated tumor infiltration of inflammatory antigen-presenting cells (APC) expressing relatively higher levels of the T-cell costimulatory ligands CD70, CD80, and CD86. Cell death triggered by cisplatin was associated with the release of at least 19 proteins in the tumor environment that could act as damage-associated molecular patterns and upregulate costimulatory molecules, either alone or in concert, but the responsible proteins remain unknown. Essentially, the curative effect of cisplatin was abrogated in mice lacking expression of CD80 and CD86 on APCs. Furthermore, cisplatin treatment was improved by CTLA-4 blockade, which increases the availability of CD80/86 to bind to CD28. In contrast, there was no effect of CD27 stimulation, which replaces CD70 interaction. At the cisplatin MTD, cure rates could also be increased by vaccination with synthetic long peptides, whereas cures could also be achieved at similar rates at 80% of the MTD with reduced side effects. Our findings reveal an essential basis for the immunogenic properties of cisplatin, which are mediated by the induction of costimulatory signals for CD8+T-cell-dependent tumor destruction. Cancer Res; 76(20); 6017-29. ©2016 AACR.
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors: Elham
authors: E
authors: Beyranvand Nejad
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors: Tetje C
authors: TC
authors: van der Sluis
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors: Suzanne
authors: S
authors: van Duikeren
authors: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Hideo
authors: H
authors: Yagita
authors: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
authors: George M
authors: GM
authors: Janssen
authors: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
authors: Peter A
authors: PA
authors: van Veelen
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. ISA Pharmaceuticals, Leiden, the Netherlands.
authors: Cornelis J M
authors: CJ
authors: Melief
authors: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Sjoerd H
authors: SH
authors: van der Burg
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. R.Arens@lumc.nl.
authors: Ramon
authors: R
authors: Arens
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen / Q000502:physiology*; D053282:CD27 Ligand / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002945:Cisplatin / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D014611:Vaccination
chemical_list: D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D053282:CD27 Ligand; C497964:CD86 protein, human; D007371:Interferon-gamma; D002945:Cisplatin