CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis.
CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis.
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DOI：
10.1371/journal.pone.0020702
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Hix LM;Shi YH;Brutkiewicz RR;Stein PL;Wang CR;Zhang M
肿瘤耐受性和免疫抑制仍然是利用免疫系统根除乳腺癌的免疫疗法有效性的巨大障碍。本实验室建立了一种新的乳腺癌转移同基因小鼠模型，用于研究乳腺癌的免疫调节机制。对从这些小鼠分离的低转移和高转移肿瘤细胞的比较分析揭示了与癌症免疫控制相关的几个重要的基因变化，包括高转移肿瘤细胞中cd1d1的显著下调。小鼠的cd1d1基因编码MHC I类分子CD1d，它将糖脂抗原呈递给一种特殊的T细胞亚群，称为自然杀伤T(NKT)细胞。我们假设，乳腺癌细胞通过下调CD1d和随后逃避NKT介导的抗肿瘤免疫，获得了更高的转移肿瘤进展的可能性。在这项研究中，我们在乳腺癌转移的小鼠模型中证明，在体外和体内，肿瘤下调CD1d以CD1d依赖的方式抑制iNKT介导的抗肿瘤免疫并促进转移性乳腺癌的进展。利用NKT基因缺陷的转基因小鼠模型，我们证明了I型和II型NKT细胞在调节CD1d表达的乳腺肿瘤的抗肿瘤免疫方面的重要差异。这项研究的结果强调了在制定基于NKT的免疫疗法预防和治疗转移性乳腺癌时，确定肿瘤CD1d表达状态的重要性。
Tumor tolerance and immune suppression remain formidable obstacles to the efficacy of immunotherapies that harness the immune system to eradicate breast cancer. A novel syngeneic mouse model of breast cancer metastasis was developed in our lab to investigate mechanisms of immune regulation of breast cancer. Comparative analysis of low-metastatic vs. highly metastatic tumor cells isolated from these mice revealed several important genetic alterations related to immune control of cancer, including a significant downregulation of cd1d1 in the highly metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I-like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells known as natural killer T (NKT) cells. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression. In this study, we demonstrate in a mouse model of breast cancer metastasis that tumor downregulation of CD1d inhibits iNKT-mediated antitumor immunity and promotes metastatic breast cancer progression in a CD1d-dependent manner in vitro and in vivo. Using NKT-deficient transgenic mouse models, we demonstrate important differences between type I and type II NKT cells in their ability to regulate antitumor immunity of CD1d-expressing breast tumors. The results of this study emphasize the importance of determining the CD1d expression status of the tumor when tailoring NKT-based immunotherapies for the prevention and treatment of metastatic breast cancer.
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