STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer.
STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer.
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DOI：
10.1158/2326-6066.cir-13-0123
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发表时间：
2014-09
影响因子：
10.1
通讯作者：
Gravekamp C
中科院分区：
文献类型：
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作者：
Chandra D;Quispe-Tintaya W;Jahangir A;Asafu-Adjei D;Ramos I;Sintim HO;Zhou J;Hayakawa Y;Karaolis DK;Gravekamp C
癌症疫苗接种可能是我们预防或治疗转移性癌症的最佳和最良性的选择。然而，肿瘤微环境（TME）中的免疫抑制阻碍了突破。在这项研究中，我们分析了环二鸟苷酸（c-di-GMP），一种干扰素基因（STING）刺激剂的配体，是否可以克服免疫抑制并改善针对转移性乳腺癌的疫苗接种。用表达肿瘤相关抗原Mage-b（LM-Mb）的基于减毒单核细胞增生李斯特菌（LM）的疫苗治疗性免疫患有转移性乳腺癌的小鼠（4 T1模型），然后用多个低剂量的c-di-GMP（0.01 nmol）。这导致了所有转移的显著和几乎消除。实验表明，c-di-GMP靶向骨髓源性抑制细胞（MDSC）和肿瘤细胞。低剂量的c-di-GMP显著增加MDSC的IL-12产生，与改善的T细胞对Mage-b的应答相关，而高剂量的c-di-GMP（范围15-150 nmol）激活4 T1肿瘤细胞中的半胱天冬酶-3并直接杀死肿瘤细胞。基于这些结果，我们在4 T1模型中测试了高剂量c-di-GMP（150 nmol）的一次给药，随后重复给药低剂量c-di-GMP（0.01 nmol），并且发现与LM-Mb和c-di-GMP的组合相比具有相同的功效。这与CD 8 T细胞对肿瘤相关抗原（TAA）Mage-b和Survivin的应答改善的机制相关，最有可能是通过来自c-di-GMP-杀伤的4 T1肿瘤细胞的这些TAA的交叉呈递，以及通过c-di-GMP-激活的TAA特异性T细胞。我们的研究结果表明，通过c-di-GMP激活STING依赖性通路对于癌症免疫治疗具有高度吸引力。
Cancer vaccination may be our best and most benign option for preventing or treating metastatic cancer. However, breakthroughs are hampered by immune suppression in the tumor microenvironment (TME). In this study, we analyzed whether cyclic di-guanylate (c-di-GMP), a ligand for stimulator of interferon genes (STING), could overcome immune suppression and improve vaccination against metastatic breast cancer. Mice with metastatic breast cancer (4T1 model) were therapeutically immunized with an attenuated Listeria monocytogenes (LM)-based vaccine, expressing tumor-associated antigen Mage-b (LM-Mb), followed by multiple low doses of c-di-GMP (0.01 nmol). This resulted in a striking and near elimination of all metastases. Experiments revealed that c-di-GMP targets myeloid-derived suppressor cells (MDSC) and tumor cells. Low doses of c-di-GMP significantly increased the production of IL-12 by MDSCs, in correlation with improved T-cell responses to Mage-b, while high dose of c-di-GMP (range 15–150 nmol) activated caspase-3 in the 4T1 tumor cells and killed the tumor cells directly. Based on these results we tested one administration of high dose c-di-GMP (150 nmol) followed by repeated administrations of low dose c-di-GMP (0.01 nmol) in the 4T1 model, and found equal efficacy compared to the combination of LM-Mb and c-di-GMP. This correlated with a mechanism of improved CD8 T-cell responses to tumor-associated antigens (TAA) Mage-b and Survivin, most likely through cross-presentation of these TAAs from c-di-GMP-killed 4T1 tumor cells, and through c-di-GMP-activated TAA-specific T cells. Our results demonstrate that activation of STING-dependent pathways by c-di-GMP is highly attractive for cancer immunotherapy.