Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824.
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.
Department of Medicine, Division of Hematology/Oncology, Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, California, USA.
Dan D
DD
Vo
Robert M
RM
Prins
Jonathan L
JL
Begley
Timothy R
TR
Donahue
Lilah F
LF
Morris
Kevin W
KW
Bruhn
Pilar
P
de la Rocha
Meng-Yin
MY
Yang
Stephen
S
Mok
Hermes J
HJ
Garban
Noah
N
Craft
James S
JS
Economou
Francesco M
FM
Marincola
Ena
E
Wang
Antoni
A
Ribas
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000637:transplantation*
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C477361:LAQ824