Immunotargeting of the xCT Cystine/Glutamate Antiporter Potentiates the Efficacy of HER2-Targeted Immunotherapies in Breast Cancer
Immunotargeting of the xCT Cystine/Glutamate Antiporter Potentiates the Efficacy of HER2-Targeted Immunotherapies in Breast Cancer
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DOI：
10.1158/2326-6066.cir-20-0082
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发表时间：
2020-08-01
影响因子：
10.1
通讯作者：
Cavallo, Federica
中科院分区：
文献类型：
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作者：
Conti, Laura;Bolli, Elisabetta;Cavallo, Federica
尽管HER 2靶向治疗改善了HER 2（+）乳腺癌的结局，但许多患者仍会出现耐药和转移性进展。癌症干细胞（CSC）在这种耐药性和进展中发挥作用，因此将HER 2靶向与CSC抑制相结合可以改善HER 2（+）乳腺癌的管理。胱氨酸-谷氨酸反向转运蛋白（cystine-glutamate antiporter，xCT）在乳腺CSC中过表达，对它们的氧化还原平衡、自我更新和对治疗的抗性至关重要，是乳腺癌免疫治疗的潜在靶点。我们使用牛疱疹病毒-4载体开发了一种靶向HER 2和xCT的联合免疫疗法，这是一种可以赋予肿瘤抗原免疫原性的安全疫苗。用单一或组合疫苗免疫大鼠Her 2转基因的乳腺癌易感性BALB-neuT小鼠。抗HER 2疫苗接种减缓原发性肿瘤生长，而抗xCT疫苗接种主要防止转移形成。两种疫苗的组合通过介导诱导细胞毒性T细胞以及诱导抗体依赖性细胞介导的细胞毒性并阻碍癌细胞增殖的HER 2和xCT抗体而发挥互补作用。靶向xCT而非靶向HER 2的抗体直接影响CSC活力、自我更新和迁移，从而诱导xCT疫苗接种的抗转移作用。我们的研究结果为HER 2（+）乳腺癌提供了一种新的治疗方法，证明通过抗xCT疫苗接种的CSC免疫靶向与HER 2靶向免疫治疗协同作用。
Despite HER2-targeted therapies improving the outcome of HER2(+) breast cancer, many patients experience resistance and metastatic progression. Cancer stem cells (CSC) play a role in this resistance and progression, thus combining HER2 targeting with CSC inhibition could improve the management of HER2(+) breast cancer. The cystine-glutamate antiporter, xCT, is overexpressed in mammary CSCs and is crucial for their redox balance, self-renewal, and resistance to therapies, representing a potential target for breast cancer immunotherapy. We developed a combined immunotherapy targeting HER2 and xCT using the Bovine Herpes virus-4 vector, a safe vaccine that can confer immunogenicity to tumor antigens. Mammary cancer-prone BALB-neuT mice, transgenic for rat Her2, were immunized with the single or combined vaccines. Anti-HER2 vaccination slowed primary tumor growth, whereas anti-xCT vaccination primarily prevented metastasis formation. The combination of the two vaccines exerted a complementary effect by mediating the induction of cytotoxic T cells and of HER2 and xCT antibodies that induce antibody-dependent cell-mediated cytotoxicity and hinder cancer cell proliferation. Antibodies targeting xCT, but not those targeting HER2, directly affected CSC viability, self- renewal, and migration, inducing the antimetastatic effect of xCT vaccination. Our findings present a new therapy for HER2(+) breast cancer, demonstrating that CSC immunotargeting via anti-xCT vaccination synergizes with HER2-directed immunotherapy.