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Research Article

Diversity and Recognition Efficiency of T Cell Responses to Cancer

  • Tor B Stuge,

    Affiliation: Department of Medicine, Division of Hematology, Stanford University, Stanford, California, United States of America

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  • Susan P Holmes,

    Affiliation: Department of Statistics, Stanford University, Stanford, California, United States of America

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  • Sahdev Saharan,

    Affiliation: Department of Medicine, Division of Hematology, Stanford University, Stanford, California, United States of America

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  • Andrea Tuettenberg,

    Affiliation: Department of Dermatology, J. Gutenberg-University, Mainz, Germany

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  • Mario Roederer,

    Affiliation: ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

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  • Jeffrey S Weber,

    Affiliation: Norris Cancer Center, University of Southern California, Los Angeles, California, United States of America

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  • Peter P Lee

    Affiliation: Department of Medicine, Division of Hematology, Stanford University, Stanford, California, United States of America

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  • Published: November 30, 2004
  • DOI: 10.1371/journal.pmed.0010028

Reader Comments (2)

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Tumor cell recognition efficiency by T cells

Posted by plosmedicine on 30 Mar 2009 at 23:39 GMT

Author: Daniel E. Speiser
Position: No occupation was given
Institution: Ludwig Institute for Cancer Research
E-mail: daniel.speiser@hospvd.ch
Additional Authors: Jean-Charles Cerottini, Pedro Romero
Submitted Date: February 01, 2005
Published Date: February 2, 2005
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

Stuge et al. report a detailed analysis of the fine specificity of CD8+ T cells against tumor-associated antigen in melanoma patients [1]. They compared peptide vaccination-driven with naturally arising T cell responses against the HLA-A*0201 restricted melanoma peptide antigens M26 (derived from Melan-A/MART-1) and G209-2M (derived from gp100 protein). A major endpoint of this study was in vitro tumor cell recognition by T cells. Fortunately, this is increasingly used as a golden standard in the assessment of tumor specific T cells. The authors suggest that spontaneously arising antigen-specific T cell populations are qualitatively different from those induced by vaccination with heteroclitic peptides (which are altered for increased HLA-binding): Tumor cell recognition was found in nearly all T cells from the former, but only in a minority from the latter. As reported previously, these results correlated with recognition efficiency of antigenic peptides. We agree that this has considerable implication for immunotherapy and congratulate the authors for analyzing T cell recognition in great detail. However, in one point our own studies lead to different results: We repetitively found that the majority of T cells generated with the heteroclitic Melan-A M26 peptide were tumor reactive. This was the case for Melan-A specific T cell populations generated in HLA-A*0201 transgenic mice [2], in vitro [3], and in melanoma patients [4]. The latter studies also assessed T cells from vaccination-site sentinel lymph nodes, containing T cells that are very likely selected and activated by vaccination and not by the tumor.

The authors point out correctly that tetramer+ T cells comprise many cells unable to recognize and kill tumor cells in an antigen specific manner, presumably due to low T cell receptor avidity to cognate antigen. An extreme case are naive T cell populations of which the majority are unable to recognize tumor cells, despite their specific binding to MHC/peptide tetramers [5]. Therefore, it is crucial to exclude naive T cells from studies analyzing tumor recognition. HLA-A*0201+ humans (healthy individuals and melanoma patients) have 0.07 +/- 0.05 % naive Melan-A tetramer+ cells within peripheral blood CD8+ T cells [5, 6]. The three patients studied by Stuge et al. had 0.23%, 0.12% and 0.50% Melan-A tetramer+ cells. Thus, one can estimate that the studied populations from the three patients contained approximately 30%, 60% and 15% naive Melan-A specific T cells, respectively. This is only a rough estimate - tetramer analysis before vaccination, and assessment of CD45RA / CCR7 expression would give more insight. Nevertheless, it remains likely that the first two patients had considerably more naive cells than the third patient (i.e. the one without immunotherapy). In addition, naive derived CD8+ T cells have a higher clonogenic potential than activated Melan-A specific T cells from melanoma patients (unpublished). This means that overrepresentation of clones derived from naive CD8+ T cells is likely to occur when both naive and activated antigen-specific CD8+ T cells co-exist in a given lymphocyte population. As mentioned, Stuge et al. found unexpected high frequencies of T cell clones not recognizing tumor cells in the two vaccinated patients. It is conceivable that this was due to the presumably high percentages of naive Melan-A specific cells present in the populations used for generating the clones, which would provide an explanation for the discrepancy with the results of our studies [2, 3, 4].

Ethical considerations limit vaccination studies in healthy humans. In patients, candidate antigens should therefore be tested with strong adjuvants [7], to increase the likelihood that the studied responses are predominantly vaccination-driven, with only minor contribution of spontaneous T cell activation [8]. It would be desirable to directly compare vaccination with heteroclitic peptide vs. vaccination with natural peptide. However, this is hampered by the lack of ex vivo detectable responses to native peptides owing to their low immunogenicity. Another option is to analyze clonal distributions (T cell receptors) of responding T cells extensively : Further support for the notion that spontaneous (tumor driven) responses have increased potential for tumor recognition would be obtained if mono/oligoclonal T cell repertoires are indeed significantly more often found in spontaneous than vaccination-induced responses.

We certainly agree that vaccines must be optimized. Thus, more such studies are desirable, since they have high potential to lead to better understanding of the differences between clinically irrelevant and relevant T cell responses, and to rapidly identify the most promising vaccine formulations that can subsequently be tested in large scale clinical trials.

References

1. Stuge TB, Holmes SP, Saharan S, Tuettenberg A, Roederer M, et al. (2004) Diversity and Recognition Efficiency of T Cell Responses to Cancer. Plos Med 1:e28.

2. Men Y, Miconnet I, Valmori D, Rimoldi D, Cerottini J-C, et al. (1999) Assessment of immunogenicity of human Melan-A peptide analogues in HLA-A*0201/Kb transgenic mice. J Immunol 162:3566-3573.

3. Valmori D, Fonteneau JF, Maranon Lizana C, Gervois N, Lienard D, et al. (1998) Enhanced generation of specific tumor-reactive CTL in vitro by selected Melan-A/MART-1 immunodominant peptide analogs. J Immunol 160:1750-1758.

4. Ayyoub M, Zippelius A, Pittet MJ, Rimoldi D, Valmori D, et al. (2003) Activation of human melanoma reactive CD8+ T cells by vaccination with an immunogenic peptide analog derived from Melan-A/MART-1. Clin Cancer Res 9:669-677.

5. Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, et al. (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64:2865-2873.

6. Romero P, Valmori D, Pittet MJ, Zippelius A, Rimoldi D, et al. (2002) Antigenicity and immunogenicity of Melan-A/MART-1 derived peptides as targets for tumor reactive CTL in human melanoma. Immunol Rev 188:81-96.

7. Speiser DE, Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, et al. (2005) Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA and CpG oligodeoxynucleotide 7909. J Clin Invest. In press

8. Speiser DE, Rimoldi D, Batard P, Lienard D, Lejeune F, et al. (2003) Disease-driven T cell activation predicts immune responses to vaccination against melanoma. Cancer Immunity 3:12.

No competing interests declared.