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Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword?

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Abstract

The coexistence of tumor progression with a tumor-specific immune response constitutes a major paradox of tumor immunity. During the last decade, the presence of cytotoxic T lymphocytes (CTLs) recognising melanoma-associated antigens has been unequivocally demonstrated in numerous different in vivo and in vitro models. However, most often these melanoma-specific T lymphocytes do not control tumor growth. Several mechanisms that involve changes in melanoma phenotype and/or in T-cell differentiation and function could explain the inability of the immune response to control melanoma. In the last few years it has been demonstrated that cellular cytotoxicity is the result of a balance between activating signals triggered by the TCR and costimulatory molecules and inhibitory signals triggered by inhibitory receptors expressed by the CTL. Because the final outcome of the immune response against melanoma depends on the balance between activating and inhibitory signals, the expression de novo on melanoma cells of ligands for inhibitory NKRs and the down-regulation of costimulatory molecules may favor the escape of tumor cells from immunosurveillance. In this paper we review how altered expression of molecules required for T-cell costimulation could result in impaired lysis of melanoma. The modulation of antimelanoma T-cell responses by a group of receptors originally described on NK cells (NK-associated receptors) but which are now known also to be expressed on a subset of cytolytic effector cells is reviewed. We hypothesize that the expression of ligands for NKRs on melanoma cells may contribute to T-cell–mediated immune responses against melanoma either enhancing or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptors or increasing activating receptors could result in new strategies to improve T-cell–mediated rejection of melanoma.

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Abbreviations

CTL:

cytotoxic T lymphocyte

Ig:

immunoglobulin

ILT:

immunoglobulin-like transcripts

ITAM:

immunoreceptor tyrosine-based activation motif

ITIM:

immunoreceptor tyrosine-based inhibition motif

KIR:

killer cell immunoglobulin-like receptors

NK cell:

natural killer cell

NKR:

natural killer cell–associated receptor

TCR:

T-cell receptor

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Acknowledgements

This work was supported by grants QLRT-2001-00668 (Outcome and Impact of Specific Treatment in European Research on Melanoma, OISTER) and QLK6-CT2002-02283 (T cells in Ageing, T-CIA) from the 5th Framework Program of the European Union, FIS01/0478, FIS03/1383 (to R.S.); FIS00/0853 (to R.T.) from the Ministry of Health; SAF2003-05184 (to R.T.) from the Ministry of Science and Technology; and 03/2 (to R.T.) from the “Consejería de Sanidad y Consumo” Junta de Extremadura (Spain).

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  1. Department of Physiology, Immunology Unit, Veterinary Faculty, University of Extremadura, Cáceres, Spain

    Raquel Tarazona

  2. Department of Cellular Biology, Physiology and Immunology, Faculty of Medicine, University of Córdoba, Córdoba, Spain

    Javier G. Casado, Olga DelaRosa, Esther Peralbo, José Peña & Rafael Solana

  3. Department of Plastic Surgery, Reina Sofia University Hospital, Córdoba, Spain

    Rocío Soto & Luis Rioja

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  1. Raquel Tarazona
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Correspondence to Raquel Tarazona.

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This article forms part of the Symposium in Writing “Tumor escape from the immune response,” published in Vol. 53

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Tarazona, R., Casado, J.G., Soto, R. et al. Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword?. Cancer Immunol Immunother 53, 911–924 (2004). https://doi.org/10.1007/s00262-004-0507-y

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