Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin

Abstract

The mouse CD8α + 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 CD8α + 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 CD8α + 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.

CD11c: Not merely a murine DC marker, but also a useful vaccination target

“…In contrast to the CD205 study [15] discussed in the previous paragraph, Castro et al [19] in this issue of The European Journal of Immunology report that the CD11c molecule on DC is a superior vaccination target for activating both CD4 + and CD8 + T cells, even when compared to CD205. CD11c is known also as integrin aX, and forms with integrin b2 (alias CD18) the complement receptor 4.…”

“…Clinical trials have been initiated to exploit these findings for human therapy (to the author's best knowledge, no reports have been published yet). It was reported recently that antigen targeted at the C-type lectin, "DC, NK lectin group receptor-1" (DNGR-1) on CD8a + DC also facilitated potent CTL responses [15]. The lectins Dectin-1, DC-SIGN, MGL and the mannose receptor have been targeted for vaccination purposes as well [16][17][18].…”

“…CD205 [14], the mannose receptor [26] or DNGR-1 [15], all of which are expressed on CD8a + conventional DC, can supply antigen for crosspresentation. Conversely, DCIR2 and the scavenger receptor endocytose antigen only for CD4 + T cell activation [12,14,26].…”

From skin dendritic cells to a simplified classification of human and mouse dendritic cell subsets

“…Based on the transcriptomic [33], functional [30,34] and developmental [35] [31,33]. Both subsets selectively express the membrane markers CADM1 [36], CLEC9A [37][38][39] and XCR1 [33,40,41] but are negative for SIRPa. Interestingly, XCL1, the chemokine ligand for XCR1 is selectively expressed by both activated NK and CD8 1 T cells [42] and Xcl1 mRNA is stored in central memory CD8 1 T lymphocytes [41].…”

Immunogenic death of colon cancer cells treated with oxaliplatin

“…Recent data, however, suggest that, in spite of its morphological uniformity, apoptosis can follow biochemically distinct subroutines, some of which may result in immunogenic cell death (Blachere et al, 2005;Casares et al, 2005;Sancho et al, 2008;Laane et al, 2009). When murine tumor cells are treated with distinct apoptosis inducers and then injected subcutaneously, in the absence of an adjuvant, they mostly fail to elicit an immune response that would protect the animals against subsequent challenge with live tumor cells (Casares et al, 2005;Obeid et al, 2007b).…”