ARTICLE ABSTRACTPurpose: A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ∼20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response.Experimental Design: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms.Results: We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell–dependent tumor regression. Importantly, 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.Conclusions: These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119–32. ©2016 AACR.