Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions.
Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions.
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DOI：
10.1097/cji.0000000000000065
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Blattman JN
中科院分区：
文献类型：
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作者：
Lussier DM;O'Neill L;Nieves LM;McAfee MS;Holechek SA;Collins AW;Dickman P;Jacobsen J;Hingorani P;Blattman JN
骨肉瘤是儿童和青少年中最常见的骨癌。尽管 70% 的局部病变患者可以通过化疗和手术切除治愈，但转移性骨肉瘤患者通常难以治疗。大量证据表明细胞毒性 T 淋巴细胞 (CTL) 限制转移性骨肉瘤的发展。我们研究了 PD-1（一种在 CTL 上表达的抑制性 TNFR 家族蛋白）在限制免疫介导控制转移性骨肉瘤的功效中的作用。我们发现人类转移性而非原发性骨肉瘤肿瘤表达 PD-1 (PD-L1) 配体，并且肿瘤浸润性 CTL 表达 PD-1，表明该途径可能限制 CTL 对患者转移性骨肉瘤的控制。 PD-L1 也在小鼠体内建立转移的 K7M2 骨肉瘤肿瘤细胞系上表达，PD-1 在疾病进展过程中在肿瘤浸润 CTL 上表达。阻断 PD-1/PD-L1 相互作用可在体外和体内显着改善骨肉瘤反应性 CTL 的功能，从而减少转移性骨肉瘤 K7M2 小鼠模型的肿瘤负荷并提高生存率。我们的结果表明，应将阻断转移性骨肉瘤患者的 PD-1/PD-L1 相互作用作为一种治疗策略。
Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.