Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer.
Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer.
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发表时间：
2005-01
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通讯作者：
S. Demaria;N. Kawashima;Anne Marie Yang;M. Devitt;J. Babb;J. Allison;S. Formenti
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作者：
S. Demaria;N. Kawashima;Anne Marie Yang;M. Devitt;J. Babb;J. Allison;S. Formenti
目的：电离放射治疗（RT）是乳腺癌治疗的重要组成部分。尽管原发性肿瘤可以通过手术和RT成功治疗，但转移性乳腺癌仍然是一个治疗挑战。在这里，我们测试了这样的假设，即对原发性肿瘤的RT与CTLA-4阻断的组合可以引起抑制转移的抗肿瘤免疫。实验设计免疫原性差的转移性小鼠乳腺癌4 T1被用作模型。将小鼠皮下注射。用4 T1细胞，并且在13天后当原发性肿瘤的平均直径测量为5 mm时开始治疗。将小鼠随机分配到四个治疗组，接受：（1）对照IgG（IgG），（2）RT + IgG，（3）针对CTLA-4的9 H10单克隆抗体，（4）RT +9 H10。RT以12戈伊的一次或两次剂量递送至原发性肿瘤。结果与4 T1免疫原性差的事实一致，单独的9 H10对原发性肿瘤生长或存活没有任何影响。RT能够延迟原发照射肿瘤的生长，但在不存在9 H10的情况下，存活率与对照小鼠相似。相比之下，用RT +9 H10处理的小鼠具有统计学显著的存活优势。增加的存活率与肺转移形成的抑制相关，并且需要CD 8+而不是CD 4 + T细胞。结论：局部RT联合CTLA-4阻断是一种很有前途的新的免疫策略，用于免疫原性差的转移性癌症。
PURPOSE Ionizing radiation therapy (RT) is an important component in the management of breast cancer. Although the primary tumor can be successfully treated by surgery and RT, metastatic breast cancer remains a therapeutic challenge. Here we tested the hypothesis that the combination of RT to the primary tumor with CTLA-4 blockade can elicit antitumor immunity inhibiting the metastases. EXPERIMENTAL DESIGN The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were injected s.c. with 4T1 cells, and treatment was started 13 days later when the primary tumors measured 5 mm in average diameter. Mice were randomly assigned to four treatment groups receiving: (1) control IgG (IgG), (2) RT + IgG, (3) 9H10 monoclonal antibody against CTLA-4, (4) RT + 9H10. RT was delivered to the primary tumor by one or two fractions of 12 Gy. 9H10 and IgG were given i.p. thrice after RT. RESULTS Consistent with the fact that 4T1 is poorly immunogenic, 9H10 alone did not have any effect on primary tumor growth or survival. RT was able to delay the growth of the primary irradiated tumor, but in the absence of 9H10 survival was similar to that of control mice. In contrast, mice treated with RT + 9H10 had a statistically significant survival advantage. The increased survival correlated with inhibition of lung metastases formation and required CD8+ but not CD4+ T cells. CONCLUSIONS The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.