Combined Histone Deacetylase Inhibitor and Immunotherapy Shows Promise in Lung Cancer Mouse Models

A recent paper discussed how HDAC (histone deacetylase) inhibitors enhanced chemokine expression by T-cells and improved response to PD-1 (Programmed cell death protein 1) immunotherapy in lung cancer.

Tumors protect themselves from the body's immune response by increasing levels of immunosuppressive molecules such as the PD-1 ligand PD-L1. Antibodies that inhibit the interaction between PD-1 and PD- L1 have been suggested as potential anticancer agents, but studies have shown that only about 20% of lung cancer patients show a response to this approach.

To improve the performance of this class of anticancer drugs, investigators at the Moffitt Cancer Center (Tampa, FL, USA) examined whether strategies that would increase T-cell infiltration to tumors could be useful in enhancing immunotherapy response.

The investigators performed an unbiased screen of 97 FDA-approved oncology agents with ability to enhance T-cell chemokine expression in order to identify those compounds capable of augmenting the response to immunotherapy. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade.

Results published in the March 10, 2016, online edition of the journal Clinical Cancer Research revealed that HDAC inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T-cells. Using the HDACi romidepsin in mouse models, they observed increased chemokine expression, enhanced T-cell infiltration, and T-cell-dependent tumor regression. Romidepsin is a natural product obtained from the bacteria Chromobacterium violaceum, which works by blocking histone deacetylase enzymes, thus inducing apoptosis.

Romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T-cells.

"These results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment," said senior author Dr. Amer Beg, a senior member of the immunology program at the Moffitt Cancer Center.

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