Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model.
Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model.
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DOI：
10.1016/j.jhep.2016.07.044
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发表时间：
2017-01
影响因子：
25.7
通讯作者：
Staveley-O'Carroll KF
中科院分区：
文献类型：
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作者：
Li G;Liu D;Cooper TK;Kimchi ET;Qi X;Avella DM;Li N;Yang QX;Kester M;Rountree CB;Kaifi JT;Cole DJ;Rockey DC;Schell TD;Staveley-O'Carroll KF
我们在免疫功能正常的小鼠中建立了临床相关的肝细胞癌（HCC）动物模型，以阐明HCC发生和发展过程中宿主免疫与肿瘤之间的复杂对话。机制的发现已经被用来开发一种临床可行的抗肿瘤化学免疫治疗策略。采用腹腔注射四氯化碳和脾内接种致癌肝细胞相结合的方法，在免疫功能正常小鼠的纤维化肝脏中诱导进行性hcc。采用免疫和过继细胞转移（ACT）来解剖肿瘤抗原特异性免疫反应。评估了酪氨酸激酶抑制剂舒尼替尼增强肝癌患者免疫治疗的能力。这种新的小鼠模型模拟了人类HCC，并反映了其典型特征。肿瘤抗原特异性CD8+ T细胞保持naïve表型，并在早期肿瘤进展中保持反应性。肿瘤进展晚期产生循环肿瘤细胞，肿瘤迁移到引流淋巴结，肿瘤抗原特异性CD8+ T细胞的深度耗竭与PD-1hi CD8+ T细胞和调节性T细胞（Tregs）的积累有关。舒尼替尼介导的杀瘤作用和Treg抑制与抗体介导的PD-1阻断协同，有效抑制肿瘤生长和激活抗肿瘤免疫。Treg的积累和PD-1的上调提供了两种独立的机制来诱导HCC的深度免疫耐受。使用fda批准的舒尼替尼联合抗pd -1抗体的化学免疫治疗取得了显著的肿瘤控制，支持这种方法用于治疗HCC患者的翻译。
We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible antitumor chemoimmunotherapeutic strategy. Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8+ T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8+ T cells associated with accumulation of PD-1hi CD8+ T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using FDA-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients.