Nota Sjoerd P F T, Osei-Hwedieh David O, Drum David L, Wang Xinhui, Sabbatino Francesco, Ferrone Soldano, Schwab Joseph H
Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Section of Orthopaedic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Front Oncol. 2022 Aug 30;12:939166. doi: 10.3389/fonc.2022.939166. eCollection 2022.
Chondrosarcoma is a common primary bone malignancy whose phenotype increases with its histologic grade. They are relatively resistant to chemotherapy and radiation therapy limiting curative options for disseminated disease. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is highly expressed across various human cancers, including chondrosarcoma, and has restricted distribution in healthy tissues, making it an attractive target for the antibody-based therapy. CSPG4 specific chimeric antigen receptor (CAR) T cell therapies have been shown to be effective in treating other cancers such as melanoma and triple negative breast cancer. The goal of this study was to assess the prevalence of CSPG4 in human chondrosarcoma and to assess the efficacy of CSPG4 specific CAR T cells in lysing chondrosarcoma cells . Using immunohistochemistry (IHC), we stained a tissue microarray containing primary conventional and dedifferentiated chondrosarcoma from 76 patients with CSPG4 specific monoclonal antibodies (mAbs). In addition, we incubated 2 chondrosarcoma cell lines with CSPG4-targeting CAR T cells and subsequently evaluated cell survival. Our results showed medium to high expression of CSPG4 in 29 of 41 (71%) conventional chondrosarcoma tumors and in 3 of 20 (15%) dedifferentiated chondrosarcoma tumors. CSPG4 expression showed a positive association with time to metastasis and survival in both subtypes. CSPG4 CAR T treated cell lines showed a lysis of respectively >80% and 70% demonstrating CSPG4-targeted CAR T cells effective in killing CSPG4-positive chondrosarcoma tumors.
软骨肉瘤是一种常见的原发性骨恶性肿瘤，其表型随组织学分级增加而变化。它们对化疗和放疗相对耐药，限制了播散性疾病的治疗选择。硫酸软骨素蛋白聚糖4（CSPG4）是一种细胞表面蛋白聚糖，在包括软骨肉瘤在内的多种人类癌症中高度表达，而在健康组织中分布受限，这使其成为基于抗体治疗的一个有吸引力的靶点。CSPG4特异性嵌合抗原受体（CAR）T细胞疗法已被证明在治疗其他癌症如黑色素瘤和三阴性乳腺癌方面有效。本研究的目的是评估CSPG4在人类软骨肉瘤中的普遍性，并评估CSPG4特异性CAR T细胞裂解软骨肉瘤细胞的疗效。我们使用免疫组织化学（IHC），用CSPG4特异性单克隆抗体（mAb）对包含76例患者的原发性传统型和去分化型软骨肉瘤的组织微阵列进行染色。此外，我们将2种软骨肉瘤细胞系与靶向CSPG4的CAR T细胞孵育，随后评估细胞存活情况。我们的结果显示，41例传统型软骨肉瘤肿瘤中有29例（71%）CSPG4呈中到高表达，20例去分化型软骨肉瘤肿瘤中有3例（15%）CSPG4呈中到高表达。在两种亚型中，CSPG4表达与转移时间和生存率均呈正相关。经CSPG4 CAR T处理的细胞系分别显示出>80%和70%的裂解率，表明靶向CSPG4的CAR T细胞可有效杀死CSPG4阳性的软骨肉瘤肿瘤。
