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MHC-class I-restricted CD4 T cells: a nanomolar affinity TCR has improved anti-tumor efficacy in vivo compared to the micromolar wild-type TCR

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Abstract

Clinical studies with immunotherapies for cancer, including adoptive cell transfers of T cells, have shown promising results. It is now widely believed that recruitment of CD4+ helper T cells to the tumor would be favorable, as CD4+ cells play a pivotal role in cytokine secretion as well as promoting the survival, proliferation, and effector functions of tumor-specific CD8+ cytotoxic T lymphocytes. Genetically engineered high-affinity T-cell receptors (TCRs) can be introduced into CD4+ helper T cells to redirect them to recognize MHC-class I-restricted antigens, but it is not clear what affinity of the TCR will be optimal in this approach. Here, we show that CD4+ T cells expressing a high-affinity TCR (nanomolar K d value) against a class I tumor antigen mediated more effective tumor treatment than the wild-type affinity TCR (micromolar K d value). High-affinity TCRs in CD4+ cells resulted in enhanced survival and long-term persistence of effector memory T cells in a melanoma tumor model. The results suggest that TCRs with nanomolar affinity could be advantageous for tumor targeting when expressed in CD4+ T cells.

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Acknowledgments

The authors would like to thank Tom Gajewski for generously providing the B16-SIY murine melanoma cell line. We also thank Melanie Studzinski, Sydney Sherman, and Natalia Wolosowicz for experimental support. This work was supported by a grant from the Melanoma Research Alliance (to D. M. K.), by NIH grant CA097296 (to D. M. K. and H. S.), and funds from an anonymous donor (to EJR). BE was supported by a Research Fellowship of the Deutsche Forschungsgemeinschaft; J. D. S. was supported by the Samuel and Ruth Engelberg/Irvington Institute Fellowship of the Cancer Research Institute.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Neuroscience Program, University of Illinois, Urbana, IL, 61801, USA

    Carolina M. Soto & Edward J. Roy

  2. Department of Biochemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL, 61801, USA

    Jennifer D. Stone, Adam S. Chervin & David M. Kranz

  3. Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL, 60637, USA

    Boris Engels & Hans Schreiber

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  1. Carolina M. Soto
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  2. Jennifer D. Stone
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  3. Adam S. Chervin
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  4. Boris Engels
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  5. Hans Schreiber
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  6. Edward J. Roy
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  7. David M. Kranz
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Correspondence to David M. Kranz.

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Carolina M. Soto, Jennifer D. Stone and Adam S. Chervin contributed equally.

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Soto, C.M., Stone, J.D., Chervin, A.S. et al. MHC-class I-restricted CD4 T cells: a nanomolar affinity TCR has improved anti-tumor efficacy in vivo compared to the micromolar wild-type TCR. Cancer Immunol Immunother 62, 359–369 (2013). https://doi.org/10.1007/s00262-012-1336-z

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