Lussier Danielle M, O'Neill Lauren, Nieves Lizbeth M, McAfee Megan S, Holechek Susan A, Collins Andrea W, Dickman Paul, Jacobsen Jeffrey, Hingorani Pooja, Blattman Joseph N
*Molecular and Cellular Biology Graduate Program †Center for Infectious Diseases and Vaccinology §Molecular Biosciences and Biotechnology ‡Postbaccalaureate Research Education Program, School of Life Sciences, Arizona State University, Tempe ∥Center for Cancer and Blood Disorders ¶Department of Pathology and Laboratory Medicine, Phoenix Children's Hospital #Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
J Immunother. 2015 Apr;38(3):96-106. doi: 10.1097/CJI.0000000000000065.
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.
骨肉瘤是儿童和青少年中最常见的骨癌。尽管70%的局限性疾病患者通过化疗和手术切除得以治愈，但转移性骨肉瘤患者通常对治疗具有抗性。大量证据表明，细胞毒性T淋巴细胞（CTLs）可限制转移性骨肉瘤的发展。我们研究了PD-1（一种在CTLs上表达的抑制性肿瘤坏死因子受体家族蛋白）在限制免疫介导的转移性骨肉瘤控制疗效中的作用。我们发现，人类转移性骨肉瘤肿瘤（而非原发性骨肉瘤肿瘤）表达PD-1的配体（PD-L1），且肿瘤浸润性CTLs表达PD-1，这表明该途径可能会限制患者体内CTLs对转移性骨肉瘤的控制。在可在小鼠体内形成转移灶的K7M2骨肉瘤肿瘤细胞系上也表达PD-L1，且在疾病进展过程中肿瘤浸润性CTLs上表达PD-1。阻断PD-1/PD-L1相互作用可显著改善骨肉瘤反应性CTLs在体外和体内的功能，并导致转移性骨肉瘤K7M2小鼠模型中的肿瘤负荷降低和生存期延长。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。
