title: Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model.
abstract: 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.
  
  
  
  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 programmed cell death protein 1 (PD-1)hiCD8+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 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.
  
  
  
  In 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.
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors: Guangfu
authors: G
authors: Li
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors: Dai
authors: D
authors: Liu
authors: Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors: Timothy K
authors: TK
authors: Cooper
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors: Eric T
authors: ET
authors: Kimchi
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors: Xiaoqiang
authors: X
authors: Qi
authors: Radiology and Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors: Diego M
authors: DM
authors: Avella
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.
authors: Ningfei
authors: N
authors: Li
authors: Radiology and Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors: Qing X
authors: QX
authors: Yang
authors: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908.
authors: Mark
authors: M
authors: Kester
authors: Bon Secours Children's Services, Richmond, VA 23226.
authors: C Bart
authors: CB
authors: Rountree
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors: Jussuf T
authors: JT
authors: Kaifi
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors: David J
authors: DJ
authors: Cole
authors: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425.
authors: Don C
authors: DC
authors: Rockey
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors: Todd D
authors: TD
authors: Schell
authors: Department of Surgery, Division of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors: Kevin F
authors: KF
authors: Staveley-O'Carroll
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D007211:Indoles; D061026:Programmed Cell Death 1 Receptor; D011758:Pyrroles; D000077210:Sunitinib
keywords: Cancer; Chemoimmunotherapy; Circulating tumor cell (CTC); Hepatocellular cancer (HCC); Immune checkpoint; Programmed cell death protein 1 (PD-1); Regulatory T cells (Tregs); Sunitinib