CCL2 blockade augments cancer immunotherapy.
CCL2 blockade augments cancer immunotherapy.
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DOI：
10.1158/0008-5472.can-09-2326
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Albelda SM
中科院分区：
文献类型：
--
作者：
Fridlender ZG;Buchlis G;Kapoor V;Cheng G;Sun J;Singhal S;Crisanti MC;Wang LC;Heitjan D;Snyder LA;Albelda SM
由于肿瘤内存在免疫抑制环境，成功的疫苗可能需要更多的方法来改变肿瘤微环境。单核细胞趋化蛋白(如CCL2)由多种肿瘤产生，具有直接和间接免疫抑制作用。我们假设CCL2阻断将减少免疫抑制并加强疫苗免疫治疗。抗小鼠CCL2/CCL12单抗用于三种免疫治疗模型：一种是针对非小细胞肺癌细胞株表达的HPV-E7抗原，一种是针对间皮瘤细胞株表达的间皮蛋白，一种是利用表达干扰素-α的腺病毒来治疗非免疫原性非小细胞肺癌细胞系。我们评估了联合治疗对肿瘤生长的影响，并通过评估细胞毒性T细胞、免疫抑制细胞和肿瘤微环境来评估这些变化的机制。与疫苗一起注射抗CCL2/CCL12抗体显著增强了疗效，增强了肿瘤体积的缩小和大约一半的肿瘤的治愈。根据四聚体评估，联合治疗产生了更多的肿瘤内总CD8+T细胞，这些细胞更活跃，更具抗肿瘤抗原特异性。另一个重要的潜在机制是肿瘤内T调节(T-reg)细胞减少。CCL2似乎是一种关键的近端细胞因子，在肿瘤中介导免疫抑制。它的阻断通过多因素机制增强了CD8+T细胞对疫苗诱导的肿瘤的免疫应答。这些观察表明，在未来的免疫治疗试验中，应该考虑将CCL2中和与疫苗结合起来。
Since an immuno-inhibitory environment exists within tumors, successful vaccines will likely require additional approaches to alter the tumor microenvironment. Monocyte chemoattractant proteins (such as CCL2) are produced by many tumors and have both direct and indirect immuno-inhibitory effects. We hypothesized that CCL2 blockade would reduce immunosuppression and augment vaccine immunotherapy. Anti-murine-CCL2/CCL12 monoclonal antibodies were administered in three immunotherapy models: one aimed at the HPV-E7 antigen expressed by a non-small cell lung cancer line, one targeted to mesothelin expressed by a mesothelioma cell line, and one using an adenovirus expressing Interferon-α to treat a non-immunogenic, non-small cell lung cancer line. We evaluated the effect of the combination treatment on tumor growth and assessed the mechanism of these changes by evaluating cytotoxic T cells, immunosuppressive cells, and the tumor microenvironment. Administration of anti-CCL2/CCL12 antibodies along with the vaccines markedly augmented efficacy with enhanced reduction in tumor volume and cures of approximately half of the tumors. The combined treatment generated more total intra-tumoral CD8+ T-cells that were more activated and more anti-tumor antigen specific, as measured by tetramer evaluation. Another important potential mechanism was reduction in intratumoral T-regulatory (T-reg) cells. CCL2 appears to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T cell immune response to tumors elicited by vaccines via multifactorial mechanisms. These observations suggest that combining CCL2 neutralization with vaccines should be considered in future immunotherapy trials.