Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin.
The mouse CD8alpha+ DC subset excels at cross-presentation of antigen, which can elicit robust CTL responses. A receptor allowing specific antigen targeting to this subset and its equivalent in humans would therefore be useful for the induction of antitumor CTLs. Here, we have characterized a C-type lectin of the NK cell receptor group that we named DC, NK lectin group receptor-1 (DNGR-1). DNGR-1 was found to be expressed in mice at high levels by CD8+ DCs and at low levels by plasmacytoid DCs but not by other hematopoietic cells. Human DNGR-1 was also restricted in expression to a small subset of blood DCs that bear similarities to mouse CD8alpha+ DCs. The selective expression pattern and observed endocytic activity of DNGR-1 suggested that it could be used for antigen targeting to DCs. Consistent with this notion, antigen epitopes covalently coupled to an antibody specific for mouse DNGR-1 were selectively cross-presented by CD8alpha+ DCs in vivo and, when given with adjuvants, induced potent CTL responses. When the antigens corresponded to tumor-expressed peptides, treatment with the antibody conjugate and adjuvant could prevent development or mediate eradication of B16 melanoma lung pseudometastases. We conclude that DNGR-1 is a novel, highly specific marker of mouse and human DC subsets that can be exploited for CTL cross-priming and tumor therapy.
Sancho
David
D
Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom.
Mourão-Sá
Diego
D
Joffre
Olivier P
OP
Schulz
Oliver
O
Rogers
Neil C
NC
Pennington
Daniel J
DJ
Carlyle
James R
JR
Reis e Sousa
Caetano
C
D000818:Animals; D000941:Antigens / Q000737:chemistry; D016827:CD8 Antigens / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D037102:Lectins / Q000378:metabolism*; D037181:Lectins, C-Type; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008545:Melanoma / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000628:therapy*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011975:Receptors, Mitogen; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*
D000941:Antigens; D016827:CD8 Antigens; C530206:CLEC9a protein, human; C529914:Clec9a protein, mouse; D037102:Lectins; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D011975:Receptors, Mitogen