HDAC inhibition prevents transgene expression downregulation and loss-of-function in T-cell-receptor-transduced T cells.

T cells that are gene-modified with tumor-specific T cell receptors are a promising treatment for metastatic melanoma patients. In a clinical trial, we treated seven metastatic melanoma patients with autologous T cells transduced to express a tyrosinase-reactive T cell receptor (TCR) (TIL 1383I) and a truncated CD34 molecule as a selection marker. We followed transgene expression in the TCR-transduced T cells after infusion and observed that both lentiviral- and retroviral-transduced T cells lost transgene expression over time, so that by 4 weeks post-transfer, few T cells expressed either lentiviral or retroviral transgenes. Transgene expression was reactivated by stimulation with anti-CD3/anti-CD28 beads and cytokines. TCR-transduced T cell lentiviral and retroviral transgene expression was also downregulated in vitro when T cells were cultured without cytokines. Transduced T cells cultured with interleukin (IL)-15 maintained transgene expression. Culturing gene-modified T cells in the presence of histone deacetylase (HDAC) inhibitors maintained transgene expression and functional TCR-transduced T cell responses to tumor. These results implicate epigenetic processes in the loss of transgene expression in lentiviral- and retroviral-transduced T cells.

US county-level agricultural crop production typology.

OBJECTIVES: Crop production is an important variable in social, economic and environmental analyses. There is an abundance of crop data available for the United States, but we lack a typology of county-level crop production that accounts for production similarities in counties across the country. We fill this gap with a county-level classification of crop production with ten mutually exclusive categories across the contiguous United States. DATA DESCRIPTION: To create the typology we ran a cluster analysis on acreage data for 21 key crops from the United States Department of Agriculture's 2012 Agricultural Census. Prior to clustering, we estimated undisclosed county acreage values, controlled for acreage in other crop types, and removed counties with low agricultural production to produce proportional scores for each crop type in each county. We used proportional scores to control for the influence of county size in the cluster analysis and used internal and stability measures to validate the analysis. The final dataset features 2922 counties. Future research can leverage this typology as an input for county- or regional-level analysis.