title: Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death.
abstract: OBJECTIVE
  Cancer immunotherapy, such as vaccination, is an increasingly successful treatment modality, but its interaction with chemotherapy remains largely undefined. Therefore, we explored the mechanism of synergy between vaccination with synthetic long peptides (SLP) of human papillomavirus type 16 (HPV16) and cisplatin in a preclinical tumor model for HPV16.
  
  
  METHODS
  SLP vaccination in this preclinical tumor model allowed the elucidation of novel mechanisms of synergy between chemo- and immunotherapy. By analyzing the tumor immune infiltrate, we focused on the local intratumoral effects of chemotherapy, vaccination, or the combination.
  
  
  RESULTS
  Of several chemotherapeutic agents, cisplatin synergized best with SLP vaccination in tumor eradication, without requirement for the maximum-tolerated dose (MTD). Upon SLP vaccination, tumors were highly infiltrated with HPV-specific, tumor necrosis factor-α (TNFα)- and interferon-γ (IFNγ)-producing T cells. Upon combined treatment, tumor cell proliferation was significantly decreased compared with single treated and untreated tumors. Furthermore, we showed that TNFα strongly enhanced cisplatin-induced apoptotic tumor cell death in a JNK-dependent manner. This is consistent with upregulation of proapoptotic molecules and with enhanced cell death in vivo upon combined SLP vaccination and cisplatin treatment. In vivo neutralization of TNFα significantly reduced the antitumor responses induced by the combined treatment.
  
  
  CONCLUSIONS
  Taken together, our data show that peptide vaccination with cisplatin treatment leads to decreased tumor cell proliferation and TNFα-induced enhanced cisplatin-mediated killing of tumor cells, together resulting in superior tumor eradication.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Tetje C
authors.initials: TC
authors.lastname: van der Sluis
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Duikeren
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.
authors.forename: Suzanna
authors.initials: S
authors.lastname: Huppelschoten
authors.affiliation: Center for Gynaecological Oncology Amsterdam, Free University Amsterdam, the Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Elham
authors.initials: E
authors.lastname: Beyranvand Nejad
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Sloots
authors.affiliation: Department of Cell Biology, Bioceros, Utrecht, the Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Pathology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.affiliation: Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands. ISA Pharmaceuticals, Leiden, the Netherlands. c.melief@lumc.nl.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D052162:Human papillomavirus 16; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D008810:Mice, Inbred C57BL; D030361:Papillomavirus Infections / Q000150:complications; D010455:Peptides; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000473:pathology* / Q000821:virology; D014764:Viral Proteins / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D010455:Peptides; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D002945:Cisplatin