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T-cell receptor tetramer binding or the lack there of does not necessitate antigen reactivity in T-cell receptor transduced T cells

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Abstract

Genetic transfer of T-cell receptor (TCR) chains provides a means of transferring tumor antigen specificity onto an alternate T-cell population. To determine which tumor reactive TCRs are best suitable for such adoptive transfer, careful evaluation of the resulting TCR modified populations need to be performed. We have previously cloned, and expressed TCRs from melanoma, EBV, HCV, and HPV reactive T-cell clones and found that several routine indicators of T-cell function do not always predict the relative strength of a TCR. Using a combination of tetramer binding assays and antigen recognition assays, we identified TCRs that fall into three classes. One class of TCR did not bind tetramers yet resulted in cells with high avidity for antigen. A second TCR class bound tetramer but did not secrete cytokines in response to antigen. Finally, the third class of TCRs bound tetramer and reacted to antigen as would be expected. We conclude that tetramer binding is not always a good indicator of the function of a cloned TCR or the avidity of a TCR gene modified T cell. Furthermore, our data indicate that the use of tetramer binding alone to identify antigen reactive TCRs may result in the exclusion of TCRs that may be highly reactive or cross reactive to the relevant tumor antigen.

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Abbreviations

TCR:

T-cell receptor

TIL:

Tumor-infiltrating lymphocytes

TAA:

Tumor-associated antigen

AV/BV, TCR:

α/β chain variable regions

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Acknowlegments

This work was supported by generous contributions from the National Institutes of Health (CA90873, CA100240, CA97296 and CA74397). W.M. Kast holds the Walter A. Richter Cancer Research Chair. C. Yee is a Damon Runyon-Lilly Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation.

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Authors and Affiliations

  1. Department of Surgery and Committee of Immunology, The University of Chicago, 5841 South Maryland Avenue, MC7116, Chicago, IL, 60637, USA

    Gretchen E. Lyons, Jeffrey J. Roszkowski & Michael I. Nishimura

  2. Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, CF14 4XX, Cardiff, Wales, UK

    Stephen Man

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Cassian Yee

  4. Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA

    W. Martin Kast

Authors
  1. Gretchen E. Lyons
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  2. Jeffrey J. Roszkowski
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  3. Stephen Man
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  4. Cassian Yee
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  5. W. Martin Kast
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  6. Michael I. Nishimura
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Correspondence to Michael I. Nishimura.

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Lyons, G.E., Roszkowski, J.J., Man, S. et al. T-cell receptor tetramer binding or the lack there of does not necessitate antigen reactivity in T-cell receptor transduced T cells. Cancer Immunol Immunother 55, 1142–1150 (2006). https://doi.org/10.1007/s00262-005-0103-9

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