title: Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model.
abstract: The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this study we evaluated the efficacy of a novel chemoimmunotherapeutic 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 multitargeted 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.
  
  
  CONCLUSIONS
  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 chemoimmunotherapeutic approach for HCC.
authors: Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Diego M
authors: DM
authors: Avella
authors: Guangfu
authors: G
authors: Li
authors: Todd D
authors: TD
authors: Schell
authors: Dai
authors: D
authors: Liu
authors: Samuel Shao-Min
authors: SS
authors: Zhang
authors: Xi
authors: X
authors: Lou
authors: Arthur
authors: A
authors: Berg
authors: Eric T
authors: ET
authors: Kimchi
authors: Hephzibah Rani S
authors: HR
authors: Tagaram
authors: Qing
authors: Q
authors: Yang
authors: Serene
authors: S
authors: Shereef
authors: Luis S
authors: LS
authors: Garcia
authors: Mark
authors: M
authors: Kester
authors: Harriet C
authors: HC
authors: Isom
authors: C Bart
authors: CB
authors: Rountree
authors: Kevin F
authors: KF
authors: Staveley-O'Carroll
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000276:immunology / Q000637:transplantation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007121:Immunocompetence / Q000276:immunology; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011758:Pyrroles / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000077210:Sunitinib