Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
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DOI：
10.1172/jci64859
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发表时间：
2013-06-01
影响因子：
15.9
通讯作者：
Levy, Ronald
中科院分区：
文献类型：
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作者：
Marabelle, Aurelien;Kohrt, Holbrook;Levy, Ronald
通过将未甲基化的CpG核苷酸直接注射到肿瘤中来激活TLR9可以诱导治疗性免疫应答;然而，TdR最终抑制抗肿瘤免疫应答，从而限制癌症免疫疗法的功效。在荷瘤小鼠中，我们发现肿瘤内的TcR优先表达细胞表面标志物CTLA-4和OX40。我们表明，肿瘤内共注射抗CTLA-4和抗OX40以及CpG耗尽了肿瘤浸润性T细胞。这种原位免疫调节是在单个肿瘤中用低剂量抗体进行的，产生了全身性抗肿瘤免疫应答，根除了小鼠的播散性疾病。此外，这种治疗方式对已确定的CNS淋巴瘤伴软脑膜转移有效，在常规全身治疗的背景下，这些部位通常被认为是肿瘤细胞的避难所。这些结果表明，由局部免疫调节引起的抗肿瘤免疫效应物可以根除远处的肿瘤细胞。我们建议，而不是使用单克隆抗体靶向癌细胞全身，单克隆抗体可用于靶向肿瘤浸润性免疫细胞局部，从而引发全身免疫反应。
Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.