Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer

Dai Liu, Guangfu Li*, Diego M. Avella, Eric T. Kimchi, Jussuf T. Kaifi, Mark P. Rubinstein, E. Ramsay Camp, Don C. Rockey, Todd D. Schell, Kevin F. Staveley-O'Carroll

*Corresponding author for this work

Research output: Contribution to journalEditorialpeer-review

24 Scopus citations


Successful development of immunotherapeutic strategies for hepatocellular cancer (HCC) has been impeded by limited understanding of tumor-induced profound tolerance and lack of a clinically faithful HCC model. Recently, we developed a novel model that recapitulates typical features of human HCC. Using this clinically relevant model, we demonstrate that tumor growth impairs host immunity and causes a profound exhaustion of tumor antigen-specific (TAS) CD8+ T cells. Increase in frequency and suppressive function of regulatory T cells (Tregs) is critically involved in this tumor-induced immune dysfunction. We further demonstrate that sunitinib suppresses Tregs and prevents tumor-induced immune tolerance, allowing TAS immunization to activate endogenous CD8+ T cells. As a result, this combinational strategy delays tumor growth. Importantly, the additional integration of exogenous naïve TAS CD8+ T cells by adoptive cell transfer (ACT) leads to the elimination of the established tumors without recurrence and promotes long-term survival of the treated mice. Mechanistically, sunitinib treatment primes the antitumor immune response by significantly decreasing Treg frequency, reducing TGF-β and IL-10 production by Tregs, and also protecting TAS CD8+ T cells from tumor-induced deletion in the setting of HCC. Taken together, sunitinib quantitatively and qualitatively modifies Tregs to overcome tumor-induced immune deficiency, suggesting the potential of sunitinib as a therapeutic immune activator for HCC control.

Original languageEnglish (US)
Article numbere1372079
Issue number1
StatePublished - Jan 2 2018


  • CD8 T cells
  • Hepatocellular Cancer (HCC)
  • IFN-γ
  • TNF-α
  • immunotherapy
  • immunotolerance
  • murine model
  • regulatory t cell (Treg)
  • sunitinib

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology


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