Genetic immunization with a melanocytic self-antigen linked to foreign helper sequences breaks tolerance and induces autoimmunity and tumor immunity.
Mechanisms maintaining peripheral tolerance to self-antigens present a major obstacle for the development of antigen-specific melanoma vaccines, presumably because self-antigens are not able to stimulate a CD4 T-helper response. Using the melanosomal enzyme tyrosinase-related protein 2 (TRP2) expressed by melanocytes and most melanoma cells as a model self-antigen, we investigated whether linkage with a foreign immunogenic protein providing strong CD4 helper sequences would be able to circumvent tolerance and enhance the induction of antigen-specific tumor immunity. We found that genetic immunization of mice with cDNA encoding a fusion protein between enhanced green fluorescent protein (EGFP) from jellyfish and autologous murine TRP2 (EGFP.mTRP2) resulted in the stimulation of TRP2-reactive T cells in vivo. Importantly, immunization with EGFP.mTRP2 effectively protected mice against metastatic growth of B16 melanoma in the lungs and was associated with fur depigmentation as a sign of autoimmune-mediated destruction of melanocytes. Our results show that tumor vaccines consisting of self-antigens linked to immunogenic helper sequences can be successfully applied to the immunotherapy of melanoma and provide a scientific basis for the translation of this strategy in future clinical investigations.
Steitz
J
J
Department of Dermatology, J Gutenberg-University, Mainz, Germany.
Brück
J
J
Gambotto
A
A
Knop
J
J
Tüting
T
T
D000818:Animals; D015551:Autoimmunity; D015704:CD4 Antigens / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics; D019496:Cancer Vaccines / Q000008:administration & dosage*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D019496:Cancer Vaccines; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase