Bae et al. elucidate the immune cell-modulating activities of the histone deacetylase 6 inhibitor, ACY241, in bone marrow cell cultures from multiple myeloma (MM) patients. They show that ACY241 decreased levels of MM cells, MDSCs, and Tregs, reduced PD-L1 expression by tumor and Tregs, and increased HLA and CD80/86 expression in tumor and DCs. Peptide-stimulated CD8+ T cells treated with ACY241 upregulated co-stimulatory and functional markers, downregulated PD-1, and were driven to a memory phenotype via stimulation of the AKT/mTOR pathway.
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138(+) MM cells, CD4(+)CD25(+)FoxP3(+) regulatory T cells, and HLA-DR(Low/-)CD11b(+)CD33(+) myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8(+) T cells and of immune checkpoints in bone marrow cells from myeloma patients. ACY241 increased B7 (CD80, CD86) and MHC (Class I, Class II) expression on tumor and dendritic cells. We further evaluated the effect of ACY241 on antigen-specific cytotoxic T lymphocytes (CTL) generated with heteroclitic XBP1unspliced184-192 (YISPWILAV) and XBP1spliced367-375 (YLFPQLISV) peptides. ACY241 induces co-stimulatory (CD28, 41BB, CD40L, OX40) and activation (CD38) molecule expression in a dose- and time-dependent manner, and anti-tumor activities, evidenced by increased perforin/CD107a expression, IFN-gamma/IL-2/TNF-alpha production, and antigen-specific central memory CTL. These effects of ACY241 on antigen-specific memory T cells were associated with activation of downstream AKT/mTOR/p65 pathways and upregulation of transcription regulators including Bcl-6, Eomes, HIF-1 and T-bet. These studies therefore demonstrate mechanisms whereby ACY241 augments immune response, providing the rationale for its use, alone and in combination, to restore host anti-tumor immunity and improve patient outcome.
Author Info: (1) Dana-Farber Cancer Institute, Boston, MA, USA. jooeun_bae@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. jooeun_bae@dfci.harvard.edu. (2) Dana-Farber Cancer Institu
Author Info: (1) Dana-Farber Cancer Institute, Boston, MA, USA. jooeun_bae@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. jooeun_bae@dfci.harvard.edu. (2) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (3) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (4) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (5) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (6) Harvard Medical School, Boston, MA, USA. Massachusetts General Hospital, Boston, MA, USA. (7) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. VA Boston Healthcare System, Boston, MA, USA. (8) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA.
