Vaccine immunotherapy with ARNAX induces tumor-specific memory T cells and durable anti-tumor immunity in mouse models.
Vaccine immunotherapy with ARNAX induces tumor-specific memory T cells and durable anti-tumor immunity in mouse models.
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DOI：
10.1111/cas.13649
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发表时间：
2018-07
期刊：
影响因子：
5.7
通讯作者：
Matsumoto M
中科院分区：
文献类型：
--
作者：
Takeda Y;Yoshida S;Takashima K;Ishii-Mugikura N;Shime H;Seya T;Matsumoto M
免疫检查点阻断疗法使有限的癌症患者群体受益。我们之前已经证明，Toll样受体（TLR）3佐剂和肿瘤抗原的疫苗免疫疗法克服了小鼠肿瘤模型中抗程序性死亡配体1（PD-L1）的耐药性。在本研究中，将4种不同的表达卵清蛋白（OVA）的肿瘤细胞系植入同基因小鼠中，并使用ARNAX和全OVA蛋白进行抗肿瘤免疫治疗。ARNAX是一种TLR 3特异性激动剂，不会激活线粒体抗病毒信号蛋白（MAVS）通路，因此不会诱导全身性炎症。ARNAX + OVA诱导了树突状细胞引发和增殖性CTL，但仅在EG 7的PD-L1-低细胞系中实现了完全缓解。在ARNAX + OVA治疗中添加抗PD-L1抗体使EG 7的另一个PD-L1高亚系完全缓解。在该方案中，在MO 5中观察到肿瘤缩小但未缓解。我们分析了肿瘤细胞和肿瘤浸润免疫细胞，以确定与ARNAX疫苗治疗成功相关的因素。对ARNAX治疗有反应的肿瘤表达高水平的MHC I类和低水平的PD-L1。ARNAX易感肿瘤中的肿瘤浸润免疫细胞含有较少的免疫抑制性髓样细胞，PD-L1表达较低。与抗PD-L1抗体的组合不仅在肿瘤部位内起作用，而且在淋巴组织内起作用，增强了ARNAX疫苗的治疗效果。值得注意的是，ARNAX治疗诱导记忆性CD 8 + T细胞和再植入肿瘤的排斥反应。因此，ARNAX疫苗+抗PD-L1治疗能够永久缓解一些稳定呈递抗原的肿瘤。
Immunological checkpoint blockade therapies benefit a limited population of cancer patients. We have previously shown that vaccine immunotherapy with Toll‐like receptor (TLR)3‐adjuvant and tumor antigen overcomes anti‐programmed death ligand‐1 (PD‐L1) resistance in mouse tumor models. In the present study, 4 different ovalbumin (OVA)‐expressing tumor cell lines were implanted into syngeneic mice and subjected to anti‐tumor immunotherapy using ARNAX and whole OVA protein. ARNAX is a TLR3‐specific agonist that does not activate the mitochondrial antiviral‐signaling protein (MAVS) pathway, and thus does not induce systemic inflammation. Dendritic cell priming and proliferative CTL were induced by ARNAX + OVA, but complete remission was achieved only in a PD‐L1‐low cell line of EG7. Addition of anti‐PD‐L1 antibody to the ARNAX + OVA therapy brought complete remission to another PD‐L1‐high subline of EG7. Tumor shrinkage but not remission was observed in MO5 in that regimen. We analyzed tumor cells and tumor‐infiltrating immune cells to identify factors associated with successful ARNAX vaccine therapy. Tumors that responded to ARNAX therapy expressed high levels of MHC class I and low levels of PD‐L1. The tumor‐infiltrating immune cells in ARNAX‐susceptible tumors contained fewer immunosuppressive myeloid cells with low PD‐L1 expression. Combination with anti‐PD‐L1 antibody functioned not only within tumor sites but also within lymphoid tissues, augmenting the therapeutic efficacy of the ARNAX vaccine. Notably, ARNAX therapy induced memory CD8+ T cells and rejection of reimplanted tumors. Thus, ARNAX vaccine + anti‐PD‐L1 therapy enabled permanent remission against some tumors that stably present antigens.
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PD-1和PD-L1检查点信号传导抑制癌症免疫疗法：机制，组合和临床结果。
影响因子：
5.6
作者：
Alsaab HO;Sau S;Alzhrani R;Tatiparti K;Bhise K;Kashaw SK;Iyer AK
通讯作者：
Iyer AK
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
克服感染和癌症中的T细胞耗尽。
影响因子：
16.8
作者：
Pauken KE;Wherry EJ
通讯作者：
Wherry EJ
影响因子：
3.7
作者：
Ryu, Min Sook;Woo, Min-Yeong;Lim, In Kyoung
通讯作者：
Lim, In Kyoung
肿瘤微环境中的髓样细胞特征预测癌症的治疗反应。
影响因子：
4
作者：
Achyut BR;Arbab AS
通讯作者：
Arbab AS