Enhancement of effector CD8+ T-cell function by tumour-associated B7-H3 and modulation of its counter-receptor triggering receptor expressed on myeloid cell-like transcript 2 at tumour sites.
B7-H3 is a B7-family co-stimulatory molecule and is broadly expressed on various tissues and immune cells. Transduction of B7-H3 into some tumours enhances anti-tumour responses. We have recently found that a triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a receptor for B7-H3. Here, we examined the roles of tumour-associated B7-H3 and the involvement of TLT-2 in anti-tumour immunity. Ovalbumin (OVA)(257-264)-specific OT-I CD8(+) T cells exhibited higher cytotoxicity against B7-H3-transduced OVA-expressing tumour cells (B7-H3/E.G7) in vitro and selectively eliminated B7-H3/E.G7 cells in vivo. The presence of B7-H3 on target cells efficiently augmented CD8(+) T-cell-mediated cytotoxicity against alloantigen or OVA, whereas the presence of B7-H3 in the priming phase did not affect the induced cytotoxicity. B7-H3 transduction into five tumour cell lines efficiently reduced their tumorigenicity and regressed growth. Treatment with either anti-B7-H3 or anti-TLT-2 monoclonal antibody accelerated growth of a tumour that expressed endogenous B7-H3, suggesting a co-stimulatory role of the B7-H3-TLT-2 pathway. The TLT-2 was preferentially expressed on CD8(+) T cells in regional lymph nodes, but was down-regulated in tumour-infiltrating CD8(+) T cells. Transduction of TLT-2 into OT-I CD8(+) T cells enhanced antigen-specific cytotoxicity against both parental and B7-H3-transduced tumour cells. Our results suggest that tumour-associated B7-H3 directly augments CD8(+) T-cell effector function, possibly by ligation of TLT-2 on tumour-infiltrating CD8(+) T cells at the local tumour site.
Department of Molecular Immunology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Hiroko
H
Kobori
Masaaki
M
Hashiguchi
Jinhua
J
Piao
Moriyuki
M
Kato
Patcharee
P
Ritprajak
Miyuki
M
Azuma
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D060887:B7 Antigens; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D000099192:CD69 Antigens
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D060887:B7 Antigens; D018122:B7-1 Antigen; D016207:Cytokines; D007371:Interferon-gamma; D037181:Lectins, C-Type; D010047:Ovalbumin; D011971:Receptors, Immunologic; D000099192:CD69 Antigens; C486038:Cd276 protein, mouse; C530953:TLT-2 protein, mouse