Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer
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. Usi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1372079 |
| _version_ | 1818970318535917568 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dai Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T14:34:35Z |
| format | Article |
| id | doaj.art-0516ffea6c534568ae9148e8f9655751 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-20T14:34:35Z |
| publishDate | 2018-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-0516ffea6c534568ae9148e8f96557512022-12-21T19:37:30ZengTaylor & Francis GroupOncoImmunology2162-402X2018-01-017110.1080/2162402X.2017.13720791372079Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancerDai Liu0Guangfu Li1Diego M. Avella2Eric T. Kimchi3Jussuf T. Kaifi4Mark P. Rubinstein5E. Ramsay Camp6Don C. Rockey7Todd D. Schell8Kevin F. Staveley-O'Carroll9University of Missouri-ColumbiaUniversity of Missouri-ColumbiaUniversity of ChicagoUniversity of Missouri-ColumbiaUniversity of Missouri-ColumbiaUniversity of Missouri-ColumbiaUniversity of Missouri-ColumbiaMedical University of South CarolinaPennsylvania State University College of MedicineUniversity of Missouri-ColumbiaSuccessful 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.http://dx.doi.org/10.1080/2162402X.2017.1372079hepatocellular cancer (hcc)sunitinibimmunotoleranceimmunotherapyregulatory t cell (treg)murine modelcd8+ t cellsifn-γtnf-α |
| spellingShingle | 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 Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer OncoImmunology hepatocellular cancer (hcc) sunitinib immunotolerance immunotherapy regulatory t cell (treg) murine model cd8+ t cells ifn-γ tnf-α |
| title | Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer |
| title_full | Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer |
| title_fullStr | Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer |
| title_full_unstemmed | Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer |
| title_short | Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer |
| title_sort | sunitinib represses regulatory t cells to overcome immunotolerance in a murine model of hepatocellular cancer |
| topic | hepatocellular cancer (hcc) sunitinib immunotolerance immunotherapy regulatory t cell (treg) murine model cd8+ t cells ifn-γ tnf-α |
| url | http://dx.doi.org/10.1080/2162402X.2017.1372079 |
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