Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824.

Abstract

Tumors grow in the presence of antigen-specific T cells, suggesting the existence of intrinsic cancer cell escape mechanisms. We hypothesized that a histone deacetylase (HDAC) inhibitor could sensitize tumor cells to immunotherapy because this class of agents has been reported to increase tumor antigen expression and shift gene expression to a proapoptotic milieu in cancer cells. To test this question, we treated B16 murine melanoma with the combination of the HDAC inhibitor LAQ824 and the adoptive transfer of gp100 melanoma antigen-specific pmel-1 T cells. The combined therapy significantly improved antitumor activity through several mechanisms: (a) increase in MHC and tumor-associated antigen expression by tumor cells; (b) decrease in competing endogenous lymphocytes in recipient mice, resulting in a proliferative advantage for the adoptively transferred cells; and (c) improvement in the functional activity of the adoptively transferred lymphocytes. We confirmed the beneficial effects of this HDAC inhibitor as a sensitizer to immunotherapy in a different model of prophylactic prime-boost vaccination with the melanoma antigen tyrosinase-related protein 2, which also showed a significant improvement in antitumor activity against B16 melanoma. In conclusion, the HDAC inhibitor LAQ824 significantly enhances tumor immunotherapy through effects on target tumor cells as well as improving the antitumor activity of tumor antigen-specific lymphocytes.

• Authors: Dan D Vo, Robert M Prins, Jonathan L Begley, Timothy R Donahue, Lilah F Morris, Kevin W Bruhn, Pilar de la Rocha, Meng-Yin Yang, Stephen Mok, Hermes J Garban, Noah Craft, James S Economou, Francesco M Marincola, Ena Wang, Antoni Ribas
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 22 Pg. 8693-9 (Nov 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19861533 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• LAQ824

Topics

• Adoptive Transfer (methods)
• Animals
• Cell Line, Tumor
• Combined Modality Therapy
• Flow Cytometry
• Gene Expression
• Gene Expression Profiling
• Histone Deacetylase Inhibitors (pharmacology)
• Hydroxamic Acids (pharmacology)
• Immunotherapy
• Melanoma, Experimental (immunology, therapy)
• Mice
• Mice, Inbred C57BL
• T-Lymphocytes (transplantation)