Mouse B7-H3 induces antitumor immunity

Abstract

Members of the B7 family costimulate the proliferation of lymphocytes during the initiation and maintenance of antigen-specific humoral and cell-mediated immune responses. While B7-1 and -2 are restricted to lymphoid tissues, and activate naïve T cells, recently identified members including B7-H2 and -H3 are widely expressed on nonlymphoid tissues, and regulate effector lymphocytes in the periphery. B7-H3 has properties that suggested it may display antitumor activity, including the ability to stimulate Th1 and cytotoxic T-cell responses. Here, we test this notion by determining whether intratumoral injection of an expression plasmid encoding a newly described mouse homologue of B7-H3 is able to eradicate EL-4 lymphomas. Intratumoral injection of a mouse B7-H3 pcDNA3 expression plasmid led to complete regression of 50% tumors, or otherwise significantly slowed tumor growth. Mice whose tumors completely regressed resisted a challenge with parental tumor cells, indicating systemic immunity had been generated. B7-H3-mediated antitumor immunity was mediated by CD8 + T and NK cells, with no apparent contribution from CD4 + T cells. In summary, the results indicate that B7-H3 interactions may play a role in regulating cell-mediated immune responses against cancer, and that B7-H3 is a potential therapeutic tool.

B7‐H3 promotes acute and chronic allograft rejection

“…Lastly, while our data demonstrating a positive regulatory pathway for B7-H3 are consistent with other work [9,12,14], they differ from reports showing negative regulatory functions of mB7-H3 [15,16]. The reasons for this are unclear, though certainly different targeting strategies, assays, and models were employed.…”

“…mB7-H3.Ig was also found to bind to mitogen-activated but not resting mouse T cells [11], and in line with a proposed stimulatory function of human B7-H3, Sun et al [12] demonstrated that intratumoral injection of an mB7-H3 pcDNA3 expression plasmid led to complete regression of about 50% of the tumors. Subsequent studies of intratumor expression of B7-H3 from the Chen laboratory [14] (where B7-H3 was first described) showed a costimulatory effect of B7-H3 and enhanced tumor immunity in vivo and in vitro in a mouse model.…”

“…Studies in humans and mice have focused on B7-H3 expression by APC [9][10][11][12][13][14], such that we first assessed whether allogeneic responses were diminished in B7-H3 -/-mice as a result of diminished DC costimulatory function by co-culturing irradiated stimulator DC with allogeneic responder CD4 T cells. We found that BALB/c CD4 T cells had a 13% proliferation rate after co-culture with control C57BL/6 DC for 24 h, whereas the corresponding proliferation of CD4 T cells co-cultured with B7-H3 -/-DC was halved (Fig.…”

“…The otherwise identical human B7-H3 and B7-H3b isoforms likely arose by gene duplication of two exons encoding the IgV-IgC domains of B7-H3 [11]. Mouse B7-H3 (mB7-H3) was subsequently cloned by two groups [11,12], mapped to chromosome 9 [11], and shown to have 88% amino acid sequence identity with human B7-H3, though the dual IgV-IgC structure was not found in mouse genomic DNA. Indeed, non-human primate B7-H3, like human B7-H3, is present in both single and duplicate IgV-IgC forms, whereas hamsters, like mice, possess only the single IgV-IgC form, consistent with broad evolutionary-based differences between primate and rodent B7-H3 [13].…”

Induction of T-Cell Apoptosis in Rats by Genetically Engineered Glioma Cells Expressing Granulocyte-Macrophage Colony-Stimulating Factor and B7.1

“…B7.1, a member of the B7 family, is located on the surface of antigen-presenting cells and is the natural ligand of CD28 on the T-cell surface (31,32). Through engagement of T-cell receptor with its cognate MHC molecules and B7.1 with CD28, interleukin-2-secreting CD4 + effector cells and CD8 + T cells will be maximally activated (31,32).…”