Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
Experimental Radiation Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-001197.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no effective standard therapy. Breast cancer stem-like cells (BCSCs) in primary TNBCs are reported to be responsible for metastatic spread of the disease and resistance to chemotherapy, but no available therapeutic tools target BCSCs. We previously reported that the ganglioside GD2 is highly expressed on BCSCs and that inhibition of its expression hampers TNBC growth. We therefore hypothesized that the anti-GD2 antibody dinutuximab (ch14.18) targets GD2 BCSCs and inhibits TNBC growth.
To test our hypothesis, we first determined GD2 expression via immunohistochemistry in frozen primary tumor samples from patients with TNBC (n=89). Then, we examined the effects of dinutuximab on TNBC cell adhesion, migration, and mammosphere formation in vitro and on tumor growth in vivo using TNBC cell-line and patient-derived xenograft (PDX) models.
We found that GD2 was expressed in around 60% of primary TNBC tumors at variable levels and was associated with worse overall survival of patients with TNBC (p=0.002). GD2 was found to be expressed in tumors and stroma, but normal ducts and lobules in adjacent tissues have shown low or no GD2 staining, indicating that GD2 is potentially a novel biomarker for tumor and its microenvironment. Treatment with dinutuximab significantly decreased adhesion and migration of MDA-MB-231 and SUM159 TNBC cells. Moreover, dinutuximab treatment inhibited mTOR signaling, which has been shown to be regulated by GD2 in BCSCs. Dinutuximab also reduced tumor growth in nude mice bearing TNBC cell-line xenografts. Finally, dinutuximab in combination with activated natural killer cells inhibited tumor growth in a TNBC PDX model and improved overall survival of tumor-bearing mice.
Dinutuximab successfully eliminated GD2 cells and reduced tumor growth in both in vivo models. Our data provide proof-of-concept for the criticality of GD2 in BCSCs and demonstrate the potential of dinutuximab as a novel therapeutic approach for TNBC.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，目前尚无有效的标准治疗方法。原发性 TNBC 中的乳腺癌干细胞样细胞（BCSCs）被认为是导致疾病转移和化疗耐药的原因，但目前尚无针对 BCSCs 的治疗工具。我们之前报道过，神经节苷脂 GD2 在 BCSCs 上高度表达，抑制其表达会阻碍 TNBC 的生长。因此，我们假设抗 GD2 抗体 dinutuximab（ch14.18）靶向 GD2 BCSCs 并抑制 TNBC 生长。
为了验证我们的假设，我们首先通过免疫组化法检测了 89 例 TNBC 患者冷冻原发肿瘤样本中 GD2 的表达。然后，我们使用 TNBC 细胞系和患者来源的异种移植（PDX）模型，在体外研究了 dinutuximab 对 TNBC 细胞黏附、迁移和类乳腺球体形成的影响，以及在体内对肿瘤生长的影响。
我们发现，GD2 在约 60%的原发性 TNBC 肿瘤中呈不同水平表达，与 TNBC 患者的总生存时间较差相关（p=0.002）。GD2 不仅在肿瘤组织和基质中表达，而且在相邻组织中的正常导管和小叶中也有低表达或无表达，这表明 GD2 可能是肿瘤及其微环境的一种新的生物标志物。用 dinutuximab 治疗后，MDA-MB-231 和 SUM159 TNBC 细胞的黏附和迁移明显减少。此外，dinutuximab 治疗还抑制了 BCSCs 中已被证明受 GD2 调节的 mTOR 信号通路。dinutuximab 还抑制了携带 TNBC 细胞系异种移植物的裸鼠的肿瘤生长。最后，dinutuximab 与活化的自然杀伤细胞联合使用可抑制 TNBC PDX 模型中的肿瘤生长并提高荷瘤小鼠的总生存率。
dinutuximab 成功消除了 GD2 细胞并减少了两种体内模型中的肿瘤生长。我们的数据为 GD2 在 BCSCs 中的重要性提供了概念验证，并证明了 dinutuximab 作为 TNBC 新型治疗方法的潜力。
