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

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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. CD4−CD8− 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.

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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

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Acknowledgments

This work was supported by the Norwegian Cancer Society and ENACT. The authors thank doctors and nurses at the study hospitals for excellent clinical follow-up and patient care. Special thanks to S. Aamdal, P. Brunsvig, T. Buanes, B. Solheim, I.K. Bukholm, L.R. Braathen, M. Gjertsen and A. Bakka. We also thank H.G. Russnes, H. Vaalerhaugen and T. Seremet for valuable help on TCR clonotype mapping.

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Authors and Affiliations

  1. Section for Immunotherapy, Department of Immunology, Cancer Research Institute, The Norwegian Radium Hospital, Rikshospitalet University Hospital, Medical Faculty, University of Oslo, 0310, Oslo, Norway

    Jon Amund Kyte, Sissel Trachsel, Kari Lislerud & Gustav Gaudernack

  2. Department of Clinical Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

    Jon Amund Kyte

  3. Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway

    Bente Risberg

  4. Department of Hematology, Center for Cancer Immune Therapy, Herlev University Hospital, 54P4, 2730, Herlev, Denmark

    Per thor Straten

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  1. Jon Amund Kyte
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Correspondence to Jon Amund Kyte.

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Kyte, J.A., Trachsel, S., Risberg, B. et al. Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunol Immunother 58, 1609–1626 (2009). https://doi.org/10.1007/s00262-009-0670-2

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