The ligands for programmed cell death 1 (PD-1), an immunoinhibitory receptor belonging to CD28/cytotoxic T lymphocyte antigen 4 family, are PD-1 ligand 1 and 2 (PD-Ls). Recent reports suggest that the aberrant expression of PD-Ls on tumor cells impairs antitumor immunity, resulting in the immune evasion of the tumor cells. Although an inverse correlation between the expression level of PD-Ls and patients' prognosis has been reported for several malignant tumors, the follow-up period was limited because of the lack of the antibody (Ab) applicable to paraffin-embedded specimens. Here we generated a new Ab against PD-1 ligand 1 (PD-L1) and analyzed the expression level of PD-Ls in human ovarian cancer using paraffin-embedded specimens. Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-1 ligand 2 also had a poorer prognosis, the difference was not statistically significant. A significant inverse correlation was observed between PD-L1 expression and the intraepithelial CD8 ؉ T lymphocyte count, suggesting that PD-L1 on tumor cells directly suppresses antitumor CD8 ؉ T cells. Multivariate analysis showed the expression of PD-L1 on tumor cells and intraepithelial CD8 ؉ T lymphocyte count are independent prognostic factors. The PD-1/ PD-L pathway can be a good target for restoring antitumor immunity in ovarian cancer.costimulation ͉ tumor immunity ͉ immunohistochemistry

coreceptor ͉ costimulation ͉ inhibitory receptor

Programmed cell death-1 (PD-1) is an inhibitory receptor and plays an important role in the regulation of ab T cells. Little is known, however, about the role of PD-1 in cd T cells. In this study, we investigated the expression and function of PD-1 in human cd T cells. Expression of PD-1 was rapidly induced in primary cd T cells following antigenic stimulation, and the PD-1 1 cd T cells produced IL-2. When PD-1 1 cd T cells were stimulated with Daudi cells with and without programmed cell death ligand-1 (PD-L1) expression, the levels of IFN-c production and cytotoxicity in response to PD-L1 1 Daudi cells were diminished compared to the levels seen in response to PD-L1 À Daudi cells. The attenuated effector functions were reversed by anti-PD-L1 mAb. When PD-1 1 cd T cells were challenged by PD-L1 1 tumors pretreated with zoledronate (Zol), which induced cd TCR-mediated signaling, the resulting reduction in cytokine production was only slight to moderate compared to the reduction seen when PD-1 1 cd T cells were challenged by PD-L1 À tumors. In addition, cytotoxic activity of PD-1 1 cd T cells against Zol-treated PD-L1 1 tumors was comparable to that against Zol-treated PD-L1 À tumors. These results suggest that TCR triggering may partially overcome the inhibitory effect of PD-1 in cd T cells.Keywords: cd T cells . Phosphoantigen . PD-1 . PD-L1 . Tumor Supporting Information available online IntroductionHuman Vg2Jg1.2Vd2 (also termed Vg9JPVd2)-bearing gd T cells recognize the so-called phosphoantigens, a group consisting of isopentenyl pyrophosphate (IPP) and related metabolites derived from microbial pathogens in a gd TCR-dependent manner [1][2][3][4]. One of the most potent naturally occurring phosphoantigens is (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMB-PP), which is derived from the 2-C-methy-D-erythritol-4-phosphate/ 1-deoxy-D-xylulose-5-phosphate pathway, an isoprenoid-biosynthetic pathway unique to certain microbes and plants [5,6]; we and others have previously reported that the subset of gd T cells [7,8]. A growing body of evidence shows that N-BPs inhibit farnesyl pyrophosphate synthase downstream of IPP in the mammalian mevalonate pathway [9,10]. It has been suggested that the resulting intracellular accumulation of IPP in the tumor cells allows gd T cells to recognize the tumor cells [11,12], although the exact mechanisms whereby this may occur remain to be identified. An increase in intracellular IPP may also occur spontaneously in certain tumor cells [13,14]. Based on these results, it has been proposed that gd T cells may be involved in surveillance for cellular metabolic stress [15,16]. Activated gd T cells produce various cytokines including IFN-g and TNF-a and also exhibit potent cytotoxic activity [17,18], and thus may serve as potential effector cells against tumors [19]. The membrane protein known as programmed cell death-1 (PD-1) is a member of the immunoglobulin superfamily, which is induced in ab T cells following antigenic stimulation [20]. Upon engagement with its specific ligan...

Human γδ T cells display potent cytotoxicity against various tumor cells pretreated with zoledronic acid (Zol). Zol has shown benefits when added to adjuvant endocrine therapy for patients with early-stage breast cancer or to standard chemotherapy for patients with multiple myeloma. Although γδ T cells may contribute to this additive effect, the responsiveness of γδ T cells from early-stage breast cancer patients has not been fully investigated. In this study, we determined the number, frequency, and responsiveness of Vγ2Vδ2 T cells from early- and late-stage breast cancer patients and examined the effect of IL-18 on their ex vivo expansion. The responsiveness of Vγ2Vδ2 T cells from patients with low frequencies of Vγ2Vδ2 T cells was significantly diminished. IL-18, however, enhanced ex vivo proliferative responses of Vγ2Vδ2 T cells and helper NK cells from patients with either low or high frequencies of Vγ2Vδ2 T cells. Treatment of breast cancer patients with Zol alone decreased the number of Vγ2Vδ2 T cells and reduced their ex vivo responsiveness. These results demonstrate that Zol can elicit immunological responses by γδ T cells from early-stage breast cancer patients but that frequent in vivo treatment reduces Vγ2Vδ2 T cell numbers and their responsiveness to stimulation.

Gomisin A, isolated from the fruits of Schisandra chinensis, is one of the dibenzocyclooctadiene lignans. Application of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1 μg/ear), a tumor-promoting agent, to the ears of mice induces inflammation. Among seven dibenzocyclooctadiene lignans assayed, gomisin A, gomisin J, and wuweizisu C inhibited the inflammatory activity induced by TPA in mice. The ED₅₀ of these compounds for TPA-induced inflammation was 1.4–4.4 μmol. Gomisin A, with an ED₅₀ of 1.4 μmol, showed the strongest inhibitory effect. Furthermore, at 5 μmol/mouse, it markedly suppressed the promotion effect of TPA (2.5 μg/mouse) on skin tumor formation in mice following initiation with 7,12-dimethylbenz[a]anthracene (50 μg/ mouse). It is assumed that the inhibition of tumor promotion by gomisin A is due to its anti-inflammatory activity.