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Resistance to the proapoptotic effects of interferon-gamma on melanoma cells used in patient-specific dendritic cell immunotherapy is associated with improved overall survival

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Abstract

The use of whole cell tumor vaccines and various means of loading antigen onto dendritic cells have been under investigation for over a decade. Induction of apoptosis and the exposure of immune-stimulating proteins are thought to be beneficial for the use in immunotherapy protocols, but conclusive evidence in the clinical setting has been lacking. Incubation of melanoma cell lines with interferon-gamma (IFN-γ) increased phosphatidylserine and calreticulin exposure, but not in the IFN-γ-resistant cell line Lu-1205. Short-term autologous melanoma cell lines used for loading dendritic cells for immunotherapy showed differential response to the pro-apoptotic effects of IFN-γ. These IFN-γ-treated tumor cells (TCs) were irradiated and used for loading antigen for dendritic cell therapy. A log-rank comparison of survival for patients whose TCs were found to be either sensitive (upregulated phosphatidylserine and calreticulin) or insensitive to IFN-γ revealed a strongly significant correlation to progression-free (p = 0.003) and overall survival (p = 0.002) favorably in those patients whose cell lines were resistant to the proapoptotic effect of IFN-γ. These results suggest that the use of IFN-γ in anti-melanoma dendritic cell-based immunotherapy may only be beneficial when the cells do not undergo apoptosis in response to IFN-γ and support the contention that the use of some apoptotic cells in vaccines may be detrimental.

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Acknowledgments

We would like to acknowledge Sarah Tillman and Andrea Beatty for their assistance in generating the tumor and dendritic cell lines and Amy Mattes for assistance in the cell death assays. Funding for this work was provided by the Hoag Hospital Foundation.

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Authors and Affiliations

  1. Cell Biology Laboratory, Hoag Cancer Center, 1 Hoag Drive Bldg 41, 92663, Newport Beach, CA, USA

    A. N. Cornforth, A. W. Fowler, D. J. Carbonell & R. O. Dillman

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  1. A. N. Cornforth
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  2. A. W. Fowler
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  3. D. J. Carbonell
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  4. R. O. Dillman
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Correspondence to A. N. Cornforth.

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Cornforth, A.N., Fowler, A.W., Carbonell, D.J. et al. Resistance to the proapoptotic effects of interferon-gamma on melanoma cells used in patient-specific dendritic cell immunotherapy is associated with improved overall survival. Cancer Immunol Immunother 60, 123–131 (2011). https://doi.org/10.1007/s00262-010-0925-y

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