Search

Immunotherapy is proved to be a promising therapeutic strategy against human malignancies. Evasion of immune surveillance is considered to be a major factor of malignant progression. Inhibitory receptors, especially CTLA-4 and PD-1, are found to play critical roles in the mediation of anti-tumor immune efficacy. Thus, antibodies targeting these immune checkpoints have emerged as the attractive treatment approaches to those patients with cancer. Osteosarcoma is highly malignant and current treatment remains a challenge, especially for those patients with metastasis. Despite some achievements, the effect of immunotherapy against osteosarcoma is still unsatisfactory. The present review attempts to show the role and mechanism of CTLA-4 and PD-1 in immune response and summarize the recent findings related to the effect of inhibitory receptor antibodies on the immune response against tumors, especially osteosarcoma, and the correlation between PD-1 or/and CTLA-4 expression and outcome of osteosarcoma patients. We further discuss the utilization of the combination therapy against osteosarcoma., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Preliminary studies of Vγ9Vδ2 T cells and zoledronate (ZOL) present promising reasons to exploit their immunotherapeutic potential for osteosarcoma treatment (OS). ZOL is a third-generation aminobisphosphonate (ABP) and is well established in the management of cancer-induced bone disease. However, ZOL is characterized by high tropism for bone matrix, and the efficacy of ZOL for sensitizing tumors remains to be optimized. Vγ9Vδ2 T cells are important effectors of antibody-dependent cell-mediated cytotoxicity (ADCC). In this study, we investigated whether Vγ9Vδ2 T cell-mediated killing of ZOL-pretreated OS cells could be increased by the anti-HER-2 monoclonal antibody trastuzumab (TTZ). The cytotoxic activity of Vγ9Vδ2 T cells against osteosarcoma was assessed by an MTS assay in the presence or absence of TTZ. A CD107a assay was used to measure degranulation in cytotoxic Vγ9Vδ2 T cells. Blocking studies were used to determine the effect of relative ligands on Vγ9Vδ2 T cell recognition. TTZ induced an ADCC response in the OS cell line, U2OS; however, it had no effect on another OS cell line HOS with low levels of surface HER2 expression. Although the OS cells pretreated with ZOL for clinically relevant time periods (2hours) stimulated a suboptimal immune response of Vγ9Vδ2 T cells, TTZ could further enhance the cytotoxicity of Vγ9Vδ2 T cells. These results demonstrate that combining TTZ and ZOL significantly increases the cytotoxic potential of Vγ9Vδ2 T cells. This study raises the possibility of utilizing ZOL and TTZ in Vγ9Vδ2 T cell-based immunotherapy for OS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Serum alkaline phosphatase (SALP) is commonly elevated in osteosarcoma patients. A number of studies have investigated the prognostic role of SALP level in patients with osteosarcoma but yielded inconsistent results., Method: Systematic computerized searches were performed in PubMed, Embase, and Web of Science databases for relevant original articles. The pooled hazard ratios (HRs) and relative risks (RRs) with corresponding confidence intervals (CIs) were calculated to assess the prognostic value of SALP level., Results: Finally, 21 studies comprising 3228 patients were included. Overall, the pooled HRs of SALP suggested that elevated level had an unfavorable impact on osteosarcoma patients' overall survival (OS) (HR = 1.82; 95% CI: 1.61-2.06; p < 0.001) and event-free survival (EFS) (HR = 1.97; 95% CI: 1.61-2.42; p < 0.001). Combined RRs of SALP indicated that elevated level was associated with presence of metastasis at diagnosis (RR = 5.55; 95% CI: 1.61-9.49; p = 0.006). No significantly different results were obtained after stratified by variables of age range, cancer stage, sample size, and geographic region., Conclusion: This meta-analysis demonstrated that high SALP level is significantly associated with poor OS or EFS rate and presence of metastasis at diagnosis. SALP level is a convenient and effective biomarker of prognosis for osteosarcoma.

Aim: To investigate the amplification and cytotoxicity of γδ T cells in peripheral blood mononuclear cells (PBMCs) of healthy donors and osteosarcoma patients stimulated by zoledronate (Zol) and IL-2., Methods: PBMCs from healthy donors and osteosarcoma patients were stimulated with IL-2 and Zol+IL-2, respectively. After 14-day culture, the purity of γδ T cells was assessed by flow cytometry. The cytotoxicity of γδ T cells against target cells was analyzed using a standard lactate dehydrogenase release assay with γδ T lymphocyte-sensitive Daudi cells, γδ T lymphocyte-resistant Raji cells and human osteoblast cell line, hFOB, as the target cells., Results: After 2-week culture ex vivo of PBMCs from healthy donors and osteosarcoma patients, compared with stimulation of IL-2, Zol+IL-2 significantly promoted the amplification of γδ T cells. In addition, γδ T cells showed the higher cytotoxicity against Daudi cells, but no cytotoxic effect on normal cells like hFOB., Conclusion: γδ T cells of high purity and high cytotoxicity can be obtained by the stimulation of Zol combined with IL-2 on PBMCs from healthy donors and osteosarcoma patients.