Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

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• 作者：Guangfu Li¹ ; ² ; ^&dagger ; ; ^&Dagger ; ; ^{liguan@health.missouri.edu} ; Dai Liu¹ ; ² ; ^&dagger ; ; ^&Dagger ; ; Timothy K. Cooper³ ; Eric T. Kimchi¹ ; ² ; ^&Dagger ; ; Xiaoqiang Qi¹ ; ² ; ^&Dagger ; ; Diego M. Avella⁴ ; Ningfei Li¹ ; Qing X. Yang⁴ ; Mark Kester⁵ ; C. Bart Rountree⁶ ; Jussuf T. Kaifi¹ ; ² ; David J. Cole¹ ; ² ; Don C. Rockey⁷ ; Todd D. Schell⁸ ; Kevin F. Staveley-O&rsquo ; Carroll¹ ; ² ; ^&Dagger ; ; ^{ocarrollk@health.missouri.edu}
• 关键词：Hepatocellular cancer (HCC) ; Chemoimmunotherapy ; Regulatory T cells (Tregs) ; Programmed cell death protein 1 (PD-1) ; Sunitinib ; Cancer ; Circulating tumor cell (CTC) ; Immune checkpoint
• 刊名：Journal of Hepatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：66
• 期：1
• 页码：75-85
• 全文大小：2874 K
• 卷排序：66

文摘

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 anti-tumor chemoimmunotherapeutic strategy.MethodsIntraperitoneal 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.ResultsThis 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 programmed cell death protein 1 (PD-1)hi 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.ConclusionTreg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients.Lay summaryIn the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.