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Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination.
Cancer Immunol Immunother 2009; 58(10):1609-26CI

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 TGFbeta 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 TGFbeta receptor II. Cytokine profiling on the long-term survivors demonstrates high IFN gamma/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 IFN gamma(high)/IL4(low)/IL10(low) 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.

Authors+Show Affiliations

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@rr-research.noNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19221745

Citation

Kyte, Jon Amund, et al. "Unconventional Cytokine Profiles and Development of T Cell Memory in Long-term Survivors After Cancer Vaccination." Cancer Immunology, Immunotherapy : CII, vol. 58, no. 10, 2009, pp. 1609-26.
Kyte JA, 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. 2009;58(10):1609-26.
Kyte, J. A., Trachsel, S., Risberg, B., thor Straten, P., Lislerud, K., & Gaudernack, G. (2009). Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunology, Immunotherapy : CII, 58(10), pp. 1609-26. doi:10.1007/s00262-009-0670-2.
Kyte JA, et al. Unconventional Cytokine Profiles and Development of T Cell Memory in Long-term Survivors After Cancer Vaccination. Cancer Immunol Immunother. 2009;58(10):1609-26. PubMed PMID: 19221745.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. AU - Kyte,Jon Amund, AU - Trachsel,Sissel, AU - Risberg,Bente, AU - thor Straten,Per, AU - Lislerud,Kari, AU - Gaudernack,Gustav, Y1 - 2009/02/17/ PY - 2008/05/23/received PY - 2009/01/22/accepted PY - 2009/2/18/entrez PY - 2009/2/18/pubmed PY - 2009/8/14/medline SP - 1609 EP - 26 JF - Cancer immunology, immunotherapy : CII JO - Cancer Immunol. Immunother. VL - 58 IS - 10 N2 - 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 TGFbeta 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 TGFbeta receptor II. Cytokine profiling on the long-term survivors demonstrates high IFN gamma/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 IFN gamma(high)/IL4(low)/IL10(low) 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. SN - 1432-0851 UR - https://www.unboundmedicine.com/medline/citation/19221745/Unconventional_cytokine_profiles_and_development_of_T_cell_memory_in_long_term_survivors_after_cancer_vaccination_ L2 - https://dx.doi.org/10.1007/s00262-009-0670-2 DB - PRIME DP - Unbound Medicine ER -