Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model.
Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model.
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DOI：
10.1002/hep.24652
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发表时间：
2012-01
期刊：
影响因子：
13.5
通讯作者：
Staveley-O'Carroll, Kevin F.
中科院分区：
文献类型：
--
作者：
Avella, Diego M.;Li, Guangfu;Schell, Todd D.;Liu, Dai;Zhang, Samuel Shao-Min;Lou, Xi;Berg, Arthur;Kimchi, Eric T.;Tagaram, Hephzibah Rani S.;Yang, Qing;Shereef, Serene;Garcia, Luis S.;Kester, Mark;Isom, Harriet C.;Rountree, C. Bart;Staveley-O'Carroll, Kevin F.
肝细胞癌（HCC）的高死亡率和频繁的复发率表明需要新的治疗方法。在这份报告中，我们评估了一种新的化学免疫策略控制肝癌的疗效，并研究了增加抗肿瘤免疫反应的潜在机制。我们通过将来自SV 40 T抗原（Tag）转基因MTD 2小鼠的致瘤性肝细胞接种到同基因C57 BL/6小鼠的肝脏中，开发了一种新的原位肝癌小鼠模型。这些MTD 2衍生的肝细胞在肝脏内特异性地形成表达Tag的HCC肿瘤。该方法提供了在免疫活性鼠模型中测试治疗策略和抗原特异性免疫导向疗法的平台。使用该模型，我们测试了口服舒尼替尼（一种小分子多靶向受体酪氨酸激酶（RTK）抑制剂）和肿瘤抗原特异性CD 8 + T细胞过继转移联合治疗消除HCC的疗效。舒尼替尼单独治疗促进了肿瘤大小的短暂减小。舒尼替尼治疗结合肿瘤抗原特异性CD 8 + T细胞的过继转移导致消除已建立的肿瘤而不复发。体外研究表明，通过抑制STAT 3信号传导抑制HCC生长。此外，舒尼替尼治疗荷瘤小鼠与STAT 3的抑制和T细胞耐受性的阻断有关。这些发现表明舒尼替尼直接通过STAT 3途径抑制HCC肿瘤生长，并阻止肿瘤抗原特异性CD 8 + T细胞耐受，从而定义了HCC的协同化学免疫方法。
The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this report, we evaluated the efficacy of a novel chemo-immunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2-derived hepatocytes form Tag expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen specific immune-directed therapy in an immunocompetent murine model. Using this model, we tested the efficacy of a combination of oral sunitinib, a small molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen-specific CD8+ T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen-specific CD8+ T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T cell tolerance. These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8+ T cell tolerance, thus defining a synergistic chemo-immunotherapeutic approach for HCC.
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影响因子：
8
作者：
Lin, L.;Amin, R.;Gallicano, G. I.;Glasgow, E.;Jogunoori, W.;Jessup, J. M.;Zasloff, M.;Marshall, J. L.;Shetty, K.;Johnson, L.;Mishra, L.;He, A. R.
通讯作者：
He, A. R.
影响因子：
11.2
作者：
Xin H;Zhang C;Herrmann A;Du Y;Figlin R;Yu H
通讯作者：
Yu H
影响因子：
8
作者：
Amin, HM;McDonnell, TJ;Lai, R
通讯作者：
Lai, R
影响因子：
32.4
作者：
Takeda, K;Clausen, BE;Akira, S
通讯作者：
Akira, S
DOI：
10.1158/1541-7786.mcr-08-0365
发表时间：
2009-06
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Li G;Li W;Angelastro JM;Greene LA;Liu DX
通讯作者：
Liu DX