Unedited Cells Research Articles

IL-17D, natural killer cells, and macrophages collaborate to promote tumor rejection (P2097)

Abstract The process of cancer immunoediting generates a repertoire of cancer cells that can persist in immune competent hosts. In its most complex form, this process begins with the elimination of highly immunogenic unedited tumor cells followed by the eventual escape of less immunogenic, edited cells. However, it is not known whether editing can also change the global gene expression profile of developing tumor cells. Here we show using a gene microarray study that the novel cytokine interleukin 17D (IL-17D) is highly expressed in certain unedited but not edited mouse tumor cell lines or certain human tumors. Moreover, forced expression of IL-17D in edited tumor cells induced rejection by stimulating monocyte chemotactic protein 1 (MCP-1, aka CCL2) production from tumor endothelial cells leading to the recruitment of natural killer (NK) cells. We go on to show that NK cells can promote the accumulation of M1-type macrophages. Altogether, these results identify IL-17D as a novel cytokine and describe one mechanism by which IL-17D can induce tumor rejection.

Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer

The transfer of high-avidity T cell receptor (TCR) genes isolated from rare tumor-specific lymphocytes into polyclonal T cells is an attractive cancer immunotherapy strategy. However, TCR gene transfer results in competition for surface expression and inappropriate pairing between the exogenous and endogenous TCR chains, resulting in suboptimal activity and potentially harmful unpredicted antigen specificities of the resultant TCRs. We designed zinc-finger nucleases (ZFNs) that promoted the disruption of endogenous TCR β- and α-chain genes. Lymphocytes treated with ZFNs lacked surface expression of CD3-TCR and expanded with the addition of interleukin-7 (IL-7) and IL-15. After lentiviral transfer of a TCR specific for the Wilms tumor 1 (WT1) antigen, these TCR-edited cells expressed the new TCR at high levels, were easily expanded to near purity and were superior at specific antigen recognition compared to donor-matched, unedited TCR-transferred cells. In contrast to unedited TCR-transferred cells, the TCR-edited lymphocytes did not mediate off-target reactivity while maintaining their anti-tumor activity in vivo, thus showing that complete editing of T cell specificity generates tumor-specific lymphocytes with improved biosafety profiles.