Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China.
Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China.
J Immunother Cancer. 2023 Apr;11(4). doi: 10.1136/jitc-2023-006808.
Chordoma is an extremely rare, locally aggressive malignant bone tumor originating from undifferentiated embryonic remnants. There are no effective therapeutic strategies for chordoma. Herein, we aimed to explore cellular interactions within the chordoma immune microenvironment and provide new therapeutic targets.
Spectrum flow cytometry and multiplex immunofluorescence (IF) staining were used to investigate the immune microenvironment of chordoma. Cell Counting Kit-8, Edu, clone formation, Transwell, and healing assays were used to validate tumor functions. Flow cytometry and Transwell assays were used to analyze macrophage phenotype and chemotaxis alterations. Immunohistochemistry, IF, western blot, PCR, and ELISA assays were used to analyze molecular expression. An organoid model and a xenograft mouse model were constructed to investigate the efficacy of maraviroc (MVC).
The chordoma immune microenvironment landscape was characterized, and we observed that chordoma exhibits a typical immune exclusion phenotype. However, macrophages infiltrating the tumor zone were also noted. Through functional assays, we demonstrated that chordoma-secreted CCL5 significantly promoted malignancy progression, macrophage recruitment, and M2 polarization. In turn, M2 macrophages markedly enhanced the proliferation, invasion, and migration viability of chordoma. CCL5 knockdown and MVC (CCL5/CCR5 inhibitor) treatment both significantly inhibited chordoma malignant progression and M2 macrophage polarization. We established chordoma patient-derived organoids, wherein MVC exhibited antitumor effects, especially in patient 4, with robust killing effect. MVC inhibits chordoma growth and lung metastasis in vivo.
Our study implicates that the CCL5-CCR5 axis plays an important role in the malignant progression of chordoma and the regulation of macrophages, and that the CCL5-CCR5 axis is a potential therapeutic target in chordoma.
脊索瘤是一种极其罕见的局部侵袭性恶性骨肿瘤，起源于未分化的胚胎残余物。目前尚无有效的脊索瘤治疗策略。在此，我们旨在探讨脊索瘤免疫微环境中的细胞相互作用，并提供新的治疗靶点。
采用流式细胞术和多重免疫荧光（IF）染色分析脊索瘤的免疫微环境。使用细胞计数试剂盒-8（CCK-8）、EdU、克隆形成、Transwell 和划痕愈合实验验证肿瘤功能。流式细胞术和 Transwell 实验分析巨噬细胞表型和趋化性改变。免疫组织化学、IF、Western blot、PCR 和 ELISA 实验分析分子表达。构建类器官模型和异种移植小鼠模型，以研究马拉维若（MVC）的疗效。
描绘了脊索瘤免疫微环境景观，我们观察到脊索瘤表现出典型的免疫排斥表型。然而，也观察到浸润肿瘤区的巨噬细胞。通过功能实验，我们证实了脊索瘤分泌的 CCL5 显著促进了恶性进展、巨噬细胞募集和 M2 极化。反过来，M2 巨噬细胞显著增强了脊索瘤的增殖、侵袭和迁移活力。CCL5 敲低和 MVC（CCL5/CCR5 抑制剂）治疗均显著抑制了脊索瘤的恶性进展和 M2 巨噬细胞极化。我们建立了脊索瘤患者来源的类器官，其中 MVC 表现出抗肿瘤作用，特别是在患者 4 中，具有强大的杀伤作用。MVC 在体内抑制脊索瘤的生长和肺转移。
本研究表明，CCL5-CCR5 轴在脊索瘤的恶性进展和巨噬细胞的调控中起重要作用，CCL5-CCR5 轴是脊索瘤的潜在治疗靶点。
