Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death

Clin Cancer Res. 2015 Feb 15;21(4):781-94. doi: 10.1158/1078-0432.CCR-14-2142. Epub 2014 Dec 12.


Purpose: 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.

Experimental design: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antineoplastic Agents / pharmacology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / pharmacology*
  • Cell Death / drug effects
  • Cisplatin / pharmacology*
  • Disease Models, Animal
  • Female
  • Human papillomavirus 16
  • Humans
  • Lymphocytes, Tumor-Infiltrating
  • Mice
  • Mice, Inbred C57BL
  • Papillomavirus Infections / complications
  • Peptides
  • Real-Time Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Uterine Cervical Neoplasms / immunology
  • Uterine Cervical Neoplasms / pathology*
  • Uterine Cervical Neoplasms / virology
  • Viral Proteins / immunology


  • Antineoplastic Agents
  • Cancer Vaccines
  • Peptides
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Viral Proteins
  • Cisplatin