Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue.
A recombinant antibody-lymphotoxin-alpha fusion protein induced an adaptive immune response protecting mice from melanoma. Importantly, this fusion protein elicited the formation of a lymphoid-like tissue in the tumor microenvironment containing L-selectin+ T cells and MHC class II+ antigen-presenting cells, as well as B and T cell aggregates. Furthermore, PNAd+/TCA4+ high endothelial venules were observed within the tumor, suggesting entry channels for naive T cell infiltrates. Over the course of therapy, a marked clonal expansion of certain TCR specificities occurred among tumor-infiltrating lymphocytes that displayed reactivity against melanoma cells and the TRP-2(180-188) peptide. Consequently, naive T cells may have been recruited to as well as primed and expanded in the lymphoid-like tissue induced by the lymphotoxin-alpha fusion protein at the tumor site.
Department of Dermatology, Julius-Maximilians-University, D-97080, Würzburg, Germany.
D
D
Schrama
P
P
thor Straten
W H
WH
Fischer
A D
AD
McLellan
E B
EB
Bröcker
R A
RA
Reisfeld
J C
JC
Becker
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D004729:Endothelium, Lymphatic / Q000276:immunology / Q000473:pathology; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D009372:Neoplasms, Connective Tissue / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014185:Transplantation, Isogeneic
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D008233:Lymphotoxin-alpha; D011993:Recombinant Fusion Proteins