Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation.

Abstract

Adoptive cell transfer therapies (ACTs) with cytotoxic T cells that target melanocytic antigens can achieve remissions in patients with metastatic melanomas, but tumours frequently relapse. Hypotheses explaining the acquired resistance to ACTs include the selection of antigen-deficient tumour cell variants and the induction of T-cell tolerance. However, the lack of appropriate experimental melanoma models has so far impeded clear insights into the underlying mechanisms. Here we establish an effective ACT protocol in a genetically engineered mouse melanoma model that recapitulates tumour regression, remission and relapse as seen in patients. We report the unexpected observation that melanomas acquire ACT resistance through an inflammation-induced reversible loss of melanocytic antigens. In serial transplantation experiments, melanoma cells switch between a differentiated and a dedifferentiated phenotype in response to T-cell-driven inflammatory stimuli. We identified the proinflammatory cytokine tumour necrosis factor (TNF)-α as a crucial factor that directly caused reversible dedifferentiation of mouse and human melanoma cells. Tumour cells exposed to TNF-α were poorly recognized by T cells specific for melanocytic antigens, whereas recognition by T cells specific for non-melanocytic antigens was unaffected or even increased. Our results demonstrate that the phenotypic plasticity of melanoma cells in an inflammatory microenvironment contributes to tumour relapse after initially successful T-cell immunotherapy. On the basis of our work, we propose that future ACT protocols should simultaneously target melanocytic and non-melanocytic antigens to ensure broad recognition of both differentiated and dedifferentiated melanoma cells, and include strategies to sustain T-cell effector functions by blocking immune-inhibitory mechanisms in the tumour microenvironment.

• Authors: Jennifer Landsberg, Judith Kohlmeyer, Marcel Renn, Tobias Bald, Meri Rogava, Mira Cron, Martina Fatho, Volker Lennerz, Thomas Wölfel, Michael Hölzel, Thomas Tüting
• Journal: Nature (Nature) Vol. 490 Issue 7420 Pg. 412-6 (Oct 18 2012) ISSN: 1476-4687 [Electronic] England
• PMID: 23051752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha
• gp100 Melanoma Antigen

Topics

• Adoptive Transfer
• Animals
• Cell Dedifferentiation
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Humans
• Immunotherapy
• Inflammation (immunology, pathology)
• Melanoma (immunology, metabolism, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• T-Lymphocytes, Cytotoxic (immunology, transplantation)
• Tumor Microenvironment (immunology)
• Tumor Necrosis Factor-alpha (immunology, pharmacology)
• gp100 Melanoma Antigen (metabolism)