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

Summary 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.