Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo

Luis Sanchez-Perez, Timothy Kottke, Rosa Maria Diaz, Atique Ahmed, Jill Thompson, Heung Chong, Alan Melcher, Sheri Holmen, Gregory Daniels, Richard Geoffrey Vile

Research output: Contribution to journalArticle

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Abstract

We have reported that i.d. injection of plasmids encoding hsp70 and a suicide gene transcriptionally targeted to melanocytes generates specific proinflammatory killing of melanocytes. The resulting CD8+ T cell response eradicates systemically established B16 tumors. Here, we studied the consequences of that CD8+ T cell response on the phenotype of preexisting tumor. In suboptimal protocols, the T cell response selected B16 variants, which grow extremely aggressively, are amelanotic and have lost expression of the tyrosinase and tyrosinase-related protein 2 (TRP-2) antigens. However, expression of other melanoma-associated antigens, such as gp100, was not affected. Antigen loss could be reversed by long-term growth in culture away from immune-selective pressures or within 96 hours by treatment with the demethylating agent 5-azacytidine (5-Aza). When transplanted back into syngeneic animals, variants were very poorly controlled by further vaccination. However, a combination of vaccination with 5-Aza to reactivate antigen expression in tumors in situ generated highly significant improvements in therapy over treatment with vaccine or 5-Aza alone. These data show that inflammatory killing of normal cells activates a potent T cell response targeted against a specific subset of self-antigens but can also lead to the immunoselection of tumor variants. Moreover, our data indicate that emergence of antigen loss variants may often be due to reversible epigenetic mechanisms within the tumor cells. Therefore, combination therapy using vaccination and systemic treatment with 5-Aza or other demethylating agents may have significant therapeutic benefits for antitumor immunotherapy.

Original languageEnglish (US)
Pages (from-to)2009-2017
Number of pages9
JournalCancer Research
Volume65
Issue number5
DOIs
StatePublished - Mar 1 2005

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Experimental Melanomas
Melanocytes
Azacitidine
Antigens
T-Lymphocytes
Vaccination
Neoplasms
Therapeutics
Melanoma-Specific Antigens
Monophenol Monooxygenase
Autoantigens
Epigenomics
Immunotherapy
Suicide
Plasmids
Vaccines
Phenotype
Injections
Growth
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo. / Sanchez-Perez, Luis; Kottke, Timothy; Diaz, Rosa Maria; Ahmed, Atique; Thompson, Jill; Chong, Heung; Melcher, Alan; Holmen, Sheri; Daniels, Gregory; Vile, Richard Geoffrey.

In: Cancer Research, Vol. 65, No. 5, 01.03.2005, p. 2009-2017.

Research output: Contribution to journalArticle

Sanchez-Perez, L, Kottke, T, Diaz, RM, Ahmed, A, Thompson, J, Chong, H, Melcher, A, Holmen, S, Daniels, G & Vile, RG 2005, 'Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo', Cancer Research, vol. 65, no. 5, pp. 2009-2017. https://doi.org/10.1158/0008-5472.CAN-04-3216
Sanchez-Perez, Luis ; Kottke, Timothy ; Diaz, Rosa Maria ; Ahmed, Atique ; Thompson, Jill ; Chong, Heung ; Melcher, Alan ; Holmen, Sheri ; Daniels, Gregory ; Vile, Richard Geoffrey. / Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo. In: Cancer Research. 2005 ; Vol. 65, No. 5. pp. 2009-2017.
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