Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts.
Murine studies have shown that immunologic targeting of the tumor vasculature, a key element of the tumor stroma, can lead to protective immunity in the absence of significant pathology. In the current study, we expand the scope of stroma-targeted immunotherapy to antigens expressed in tumor-associated fibroblasts, the predominant component of the stroma in most types of cancer. Mice were immunized against fibroblast activation protein (FAP), a product up-regulated in tumor-associated fibroblasts, using dendritic cells transfected with FAP mRNA. Using melanoma, carcinoma, and lymphoma models, we show that tumor growth was inhibited in tumor-bearing mice vaccinated against FAP and that the magnitude of the antitumor response was comparable to that of vaccination against tumor cell-expressed antigens. Both s.c. implanted tumors and lung metastases were susceptible to anti-FAP immunotherapy. The antitumor response could be further enhanced by augmenting the CD4+ T-cell arm of the anti-FAP immune response, achieved by using a lysosomal targeting sequence to redirect the translated FAP product into the class II presentation pathway, or by covaccination against FAP and a tumor cell-expressed antigen, tyrosinase-related protein 2. No morbidity or mortality was associated with anti-FAP vaccination except for a small delay in wound healing. The study suggests that FAP, a product which is preferentially expressed in tumor-associated fibroblasts, could function as a tumor rejection antigen in a broad range of cancers.
Lee
Jaewoo
J
Center for Translational Research, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Fassnacht
Martin
M
Nair
Smita
S
Boczkowski
David
D
Gilboa
Eli
E
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D048708:Cell Growth Processes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D010450:Endopeptidases; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D018093:Gelatinases; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive / Q000379:methods; D051907:Lysosomal Membrane Proteins / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D013945:Thymoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D014162:Transfection; D000099167:Fibroblast Activation Protein Alpha
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha