Cancer Immunology, Immunotherapy

, Volume 58, Issue 10, pp 1609–1626

Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination

Authors

    • Section for Immunotherapy, Department of Immunology, Cancer Research InstituteThe Norwegian Radium Hospital, Rikshospitalet University Hospital, Medical Faculty, University of Oslo
    • Department of Clinical Cancer ResearchThe Norwegian Radium Hospital
  • Sissel Trachsel
    • Section for Immunotherapy, Department of Immunology, Cancer Research InstituteThe Norwegian Radium Hospital, Rikshospitalet University Hospital, Medical Faculty, University of Oslo
  • Bente Risberg
    • Department of PathologyThe Norwegian Radium Hospital
  • Per thor Straten
    • Department of Hematology, Center for Cancer Immune TherapyHerlev University Hospital
  • Kari Lislerud
    • Section for Immunotherapy, Department of Immunology, Cancer Research InstituteThe Norwegian Radium Hospital, Rikshospitalet University Hospital, Medical Faculty, University of Oslo
  • Gustav Gaudernack
    • Section for Immunotherapy, Department of Immunology, Cancer Research InstituteThe Norwegian Radium Hospital, Rikshospitalet University Hospital, Medical Faculty, University of Oslo
Original Article

DOI: 10.1007/s00262-009-0670-2

Cite this article as:
Kyte, J.A., Trachsel, S., Risberg, B. et al. Cancer Immunol Immunother (2009) 58: 1609. doi:10.1007/s00262-009-0670-2

Abstract

Cancer vaccine trials frequently report on immunological responses, without any clinical benefit. This paradox may reflect the challenge of discriminating between effective and pointless immune responses and sparse knowledge on their long-term development. Here, we have analyzed T cell responses in long-term survivors after peptide vaccination. There were three main study aims: (1) to characterize the immune response in patients with a possible clinical benefit. (2) To analyze the long-term development of responses and effects of booster vaccination. (3) To investigate whether the Th1/Th2-delineation applies to cancer vaccine responses. T cell clones were generated from all nine patients studied. We find that surviving patients harbor durable tumor-specific responses against vaccine antigens from telomerase, RAS or TGFβ receptor II. Analyses of consecutive samples suggest that booster vaccination is required to induce robust T cell memory. The responses exhibit several features of possible clinical advantage, including combined T-helper and cytotoxic functionality, recognition of naturally processed antigens and diverse HLA-restriction and fine-specificity. CD4CD8 T cell clones display unconventional cytotoxicity and specifically kill tumor cells expressing mutated TGFβ receptor II. Cytokine profiling on the long-term survivors demonstrates high IFNγ/IL10-ratios, favoring immunity over tolerance, and secretion of multiple chemokines likely to mobilize the innate and adaptive immune system. Interestingly, these pro-inflammatory cytokine profiles do not follow a Th1/Th2-delineation. Most IFNγhigh/IL4low/IL10low cultures include high concentrations of hallmark Th2-cytokines IL-5 and IL-13. This does not reflect a mixture of Th1- and Th2-clones, but applies to 19/20 T cell clones confirmed to be monoclonal through TCR clonotype mapping. The present study identifies several factors that may promote clinical efficacy and suggests that cytokine profiling should not rely on the Th1/Th2-paradigm, but assess the overall inflammatory milieu and the balance between key cytokines.

Keywords

Cancer vaccinationHumanTh1/Th2CytokinesClinical efficacyT cell memory

Abbreviations

TGFβRII

Transforming growth factor β receptor II

hTERT

Human telomerase reverse transcriptase

DGGE

Denaturating gradient gel electrophoresis

IL-1ra

Interleukin 1 receptor antagonist

PDGF

Platelet derived growth factor

FGFb

Fibroblast growth factor basic

VEGF

Vascular endothelial growth factor

TA

Tumor antigen

IP-10

Interferon-inducible protein-10

Supplementary material

262_2009_670_MOESM1_ESM.pdf (1.9 mb)
Supplementary Figures (PDF 1957 kb)

Copyright information

© Springer-Verlag 2009