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Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells

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Abstract

The current therapy of uveal melanoma (UM) metastases remains inefficient, which warrants the development of new treatment modalities. For the first time we investigated the effects of retinoic acid (RA) on a panel of UM cell lines and found that RA induces morphological changes compatible with differentiation, suppresses proliferation and causes apoptosis in these cells. RA treatment resulted in an increase of p21, p27 and p53 protein levels and G1 arrest in UM cells, which correlated with significant down-modulation of surface Her2/neu proto-oncogene expression. In addition, RA-treated UM cells exhibited increased sensitivity to both MHC class I-restricted killing by cytotoxic T lymphocytes and NK cell-mediated lysis that were accompanied by more efficient conjugate formation between UM cells and killer lymphocytes. Taken together, our results implicate UM as a new target for treatment with retinoids and suggest that retinoids and T- or NK-cell based immunotherapy can have mutually enhancing effects in UM patients.

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Acknowledgments

This work has been supported by the Swedish Cancer Foundation, Swedish Research Council, the Cancer Society in Stockholm and King Gustav the Fifth Jubilee Fund. We would like to thank Mikael Hanson for his help in the preparation of the manuscript and Dr. Ashley Miller for the critical review of this manuscript.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    Simona Vertuani, Eugenia Dubrovska, Rolf Kiessling & Jelena Levitskaya

  2. Microbiology and Tumorbiology Centre, Karolinska Institutet, Stockholm, Sweden

    Victor Levitsky

  3. Department of Ophthalmology, Leiden University Medical Centre, Leiden, Netherlands

    Martine J. Jager

  4. Immune and Gene Therapy Unit, Cancer Centrum Karolinska, Karolinska Hospital, KS-ringen, R8:01, 17176, Stockholm, Sweden

    Jelena Levitskaya

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  1. Simona Vertuani
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  2. Eugenia Dubrovska
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Correspondence to Jelena Levitskaya.

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Vertuani, S., Dubrovska, E., Levitsky, V. et al. Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells. Cancer Immunol Immunother 56, 193–204 (2007). https://doi.org/10.1007/s00262-006-0185-z

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  • DOI: https://doi.org/10.1007/s00262-006-0185-z

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