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

• Published in: Oncoimmunology Vol. 7; no. 1; p. e1372079
• Main Authors: Liu, Dai, Li, Guangfu, Avella, Diego M., Kimchi, Eric T., Kaifi, Jussuf T., Rubinstein, Mark P., Camp, E. Ramsay, Rockey, Don C., Schell, Todd D., Staveley-O'Carroll, Kevin F.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.01.2018; Taylor & Francis Group
• Subjects: CD8; cd8+ t cells; Hepatocellular Cancer (HCC); IFN-γ; immunotherapy; immunotolerance; murine model; regulatory t cell (Treg); sunitinib; T cells; TNF-α; sunitinib; CD8+ T cells; IFN-γ; Hepatocellular Cancer (HCC); TNF-α; regulatory t cell (Treg); immunotherapy; immunotolerance; murine model
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2017.1372079

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.