Data from CD69 Imposes Tumor-Specific CD8<sup>+</sup> T-cell Fate in Tumor-Draining Lymph Nodes

Abstract

<div>Abstract<p>Tumor-specific CD8<sup>+</sup> T cells play a pivotal role in antitumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8<sup>+</sup> T cells are heterogeneous; Tcf1<sup>+</sup> stemlike CD8<sup>+</sup> T cells give rise to their cytotoxic progeny—Tim-3<sup>+</sup> terminally differentiated CD8<sup>+</sup> T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8<sup>+</sup> T cells can be generated within tumor-draining lymph nodes (TDLN) and that CD69 expression on tumor-specific CD8<sup>+</sup> T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8<sup>+</sup> T cells, and consequently promoted generation of functional terminally differentiated CD8<sup>+</sup> T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8<sup>+</sup> T cells, and the combined use of anti-CD69 and anti–programmed cell death protein 1 (PD-1) showed an efficient antitumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade.</p></div>