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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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.
KeywordsDendritic cells Immunotherapy Interferon-gamma Apoptosis Melanoma
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.
- 7.Lotem M, Machlenkin A, Hamburger T, Nissan A, Kadouri L, Frankenburg S et al (2009) Autologous melanoma vaccine induces antitumor and self-reactive immune responses that affect patient survival and depend on MHC class II expression on vaccine cells. Clin Cancer Res 15:4968–4977CrossRefPubMedGoogle Scholar
- 8.Fujisawa Y, Nabekura T, Nakao T, Nakamura Y, Takahashi T, Kawachi Y et al (2009) The induction of tumor-specific CD4+ T cells via major histocompatibility complex class II is required to gain optimal anti-tumor immunity against B16 melanoma cell line in tumor immunotherapy using dendritic cells. Exp Dermatol 18:396–403CrossRefPubMedGoogle Scholar
- 18.Dillman RO, Selvan SR, Schiltz PM, McClay EF, Barth NM, DePriest C et al (2009) Phase II trial of dendritic cells loaded with antigens from self-renewing, proliferating autologous tumor cells as patient-specific antitumor vaccines in patients with metastatic melanoma: final report. Cancer Biother Radiopharm 24:311–319CrossRefPubMedGoogle Scholar
- 19.Choi D, Perrin M, Hoffmann S, Chang AE, Ratanatharathorn V, Uberti J et al (1998) Dendritic cell-based vaccines in the setting of peripheral blood stem cell transplantation: CD34+ cell-depleted mobilized peripheral blood can serve as a source of potent dendritic cells. Clin Cancer Res 4:2709–2716PubMedGoogle Scholar
- 24.Selvan SR, Carbonell DJ, Fowler AW, Beatty AR, Ravindranath MH, Dillman RO (2010) Establishment of stable cell lines for personalized melanoma cell vaccine. Melanoma Res 20(4)280–292Google Scholar
- 39.Dillman RO, DePriest C, DeLeon C, Barth NM, Schwartzberg LS, Beutel LD et al (2007) Patient-specific vaccines derived from autologous tumor cell lines as active specific immunotherapy: results of exploratory phase I/II trials in patients with metastatic melanoma. Cancer Biother Radiopharm 22:309–321CrossRefPubMedGoogle Scholar