B Cells Are Critical to T-cell-Mediated Antitumor Immunity Induced by a Combined Immune-Stimulatory/Conditionally Cytotoxic Therapy for Glioblastoma
B Cells Are Critical to T-cell-Mediated Antitumor Immunity Induced by a Combined Immune-Stimulatory/Conditionally Cytotoxic Therapy for Glioblastoma
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DOI：
10.1593/neo.11024
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发表时间：
2011-10-01
期刊：
影响因子：
4.8
通讯作者：
Castro, Maria G.
中科院分区：
文献类型：
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作者：
Candolfi, Marianela;Curtin, James F.;Castro, Maria G.
我们已经证明，通过肿瘤内施用编码条件性细胞毒性分子的腺病毒载体（Ad）来修饰肿瘤微环境，HSV 1-TK和免疫刺激细胞因子，即，fms样酪氨酸激酶3配体（Flt 3L）导致胶质母细胞瘤啮齿动物模型中的T细胞依赖性肿瘤消退。我们研究了免疫介导的多形性胶质母细胞瘤消退过程中B细胞的作用。虽然Ad-TK+ Ad-Flt 3L治疗在60%的野生型（WT）小鼠中诱导肿瘤消退，但在B细胞缺陷型Igh 6（-/-）小鼠中完全失败。在Ad-TK+ Ad-Flt 3L处理的WT小鼠中检测到肿瘤特异性T细胞前体，但在Igh 6（-/-）小鼠中未检测到。在耗尽总B细胞或边缘区B细胞的WT小鼠中，治疗也失败。因为我们不能检测到针对肿瘤细胞的循环抗体，并且治疗在WT小鼠和Prdm 1（编码Blimp-1）的B细胞特异性缺失的小鼠中同样有效，其中存在B细胞但不能完全分化为抗体分泌浆细胞，所以该模型中的肿瘤消退不依赖于B细胞产生肿瘤抗原特异性免疫球蛋白。相反，B细胞似乎发挥抗原呈递细胞（APC）的作用。Ad-TK+ Ad-Flt 3 L处理导致颈部淋巴结中B细胞数量增加，这刺激了同源T细胞的增殖，并诱导抗肿瘤T细胞的克隆性扩增。我们的数据表明，B细胞作为APC，在肿瘤抗原特异性T细胞的克隆性扩增和脑肿瘤消退中发挥关键作用。
We have demonstrated that modifying the tumor microenvironment through intratumoral administration of adenoviral vectors (Ad) encoding the conditional cytotoxic molecule, i.e., HSV1-TK and the immune-stimulatory cytokine, i.e., fms-like tyrosine kinase 3 ligand (Flt3L) leads to T-cell-dependent tumor regression in rodent models of glioblastoma. We investigated the role of B cells during immune-mediated glioblastoma multiforme regression. Although treatment with Ad-TK+Ad-Flt3L induced tumor regression in 60% of wild-type (WT) mice, it completely failed in B-cell-deficient Igh6(-/-) mice. Tumor-specific T-cell precursors were detected in Ad-TK+Ad-Flt3L-treated WT mice but not in Igh6(-/-) mice. The treatment also failed in WT mice depleted of total B cells or marginal zone B cells. Because we could not detect circulating antibodies against tumor cells and the treatment was equally efficient in WT mice and in mice with B-cell-specific deletion of Prdm 1 (encoding Blimp-1), in which B cells are present but unable to fully differentiate into antibody-secreting plasma cells, tumor regression in this model is not dependent on B cells' production of tumor antigen-specific immunoglobulins. Instead, B cells seem to play a role as antigen-presenting cells (APCs). Treatment with Ad-TK+Ad-Flt3L led to an increase in the number of B cells in the cervical lymph nodes, which stimulated the proliferation of syngeneic T cells and induced clonal expansion of antitumor T cells. Our data show that B cells act as APCs, playing a critical role in clonal expansion of tumor antigen-specific T cells and brain tumor regression.