Using a clinically relevant hepatocellular carcinoma (HCC) model, Liu et al. interrogated the mechanism underlying the antitumor efficacy of sunitinib, an FDA-approved tyrosine-kinase inhibitor, and found that it decreases the frequency of tumor Tregs and subdues their tumor-enhanced immunosuppressive functions (particularly secretion of TGFβ and IL-10), leading to partial recovery of tumor antigen-specific (TAS) CD8+ T cell activity. Combining sunitinib with TAS immunization and adoptive transfer of TAS CD8+ T cells led to complete elimination of established tumors.
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 naive 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-beta 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.
Author Info: (1) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. (2) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Department of Microbio
Author Info: (1) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. (2) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Department of Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO, USA. (3) Department of Surgery, University of Chicago, IL, USA. (4) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (5) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (6) Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (7) Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (8) Department of Surgery, Medical University of South Carolina, Charleston, SC, USA; Department of Medicine, Medical University of South Carolina, Charleston, SC, USA. (9) Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, USA. (10) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA.
