Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation.
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.
Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, D-53105 Bonn, Germany.
Jennifer
J
Landsberg
Judith
J
Kohlmeyer
Marcel
M
Renn
Tobias
T
Bald
Meri
M
Rogava
Mira
M
Cron
Martina
M
Fatho
Volker
V
Lennerz
Thomas
T
Wölfel
Michael
M
Hölzel
Thomas
T
Tüting
D019264:Adoptive Transfer; D000818:Animals; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation*; D059016:Tumor Microenvironment / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D058951:gp100 Melanoma Antigen / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D058951:gp100 Melanoma Antigen