Data from Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8<sup>+</sup> T Cells and Histone Acetyltransferases

Abstract

<div>Abstract<p>NKG2D-mediated immune surveillance is crucial for inhibiting tumor growth and metastases. Malignant tumor cells often downregulate NKG2D ligands to escape from immune surveillance. High-profile studies have shown that restoring NKG2D ligand expression via genetic engineering inhibits tumor formation and progression. However, no effective <i>in vivo</i> approaches are available to restore these ligands across different types of solid tumors because the classic stress signal–dependent induction of this ligand <i>in vitro</i> is transient and has rarely been duplicated in solid tumors <i>in vivo</i>. We found that coadministration of an immune stimulatory signal (IL12) and chemotherapy (doxorubicin) restored the NKG2D ligand Rae-1 in multiple tumor types, including a human tumor model. The restored expression of NKG2D ligands was associated with tumor cell death and delay of tumor progression <i>in vivo</i>. Induction of tumor-specific NKG2D ligands required the engagement of CD8<sup>+</sup> T cells and was regulated by the histone acetyltransferases GCN5 and PCAF. The tumor-specific restoration of NKG2D ligands in a variety of tumor models, including a human tumor model, resulted in NKG2D-dependent tumor regression and extended survival time. The elucidation of a CD8<sup>+</sup> T cell–dependent mechanism suggests that activated NKG2D<sup>+</sup>CD8<sup>+</sup> T-cell therapy alone may be able to restore the NKG2D ligand in tumors. <i>Cancer Immunol Res; 5(4); 300–11. ©2017 AACR</i>.</p></div>