Abstract
<jats:title>Summary</jats:title> <jats:p> Tumor infiltrating CD8 <jats:sup>+</jats:sup> T cells (TILs) progress to a state of terminal exhaustion (Ttex) which have impaired functionality and are nonrenewable. However their precursors (Tpex) are renewable and can generate efficient effector cells. We started from the observation that melanoma patients undergoing therapy with checkpoint inhibitors show increased survival when their T cells have low <jats:italic>BCL11B</jats:italic> mRNA. In line with this, ablation of <jats:italic>Bcl11b</jats:italic> in CD8 <jats:sup>+</jats:sup> TILs conferred a superior anti-tumor response in murine melanoma and ovarian cancer models. <jats:italic>Bcl11b</jats:italic> KO TILs failed to progress to the Ttex state and retained elevated stemness. Bcl11b exerted its role by repressing expression of essential transcription factors (TF) controlling stemness, and conversely by promoting expression of exhaustion-associated TFs and inhibitory receptor genes, through complex epigenetic control. In addition, <jats:italic>Bcl11b</jats:italic> KO CD8 <jats:sup>+</jats:sup> T cells showed increased Ag-specific cytolytic activity and elevated Gzmb and Prf1 proteins, but no increase in their mRNAs, however presented higher expression of genes with role in translation. Furthermore, CRISPR-CAS9-mediated deletion of BCL11B in human TILs from a patient with poor response to adoptive cell therapy with autologous TILs, improved their cytolytic activity and promoted expression of the stemness-associated TF TCF1, underlying its potential therapeutic use. </jats:p> <jats:sec> <jats:title>HIGHLIGHTS</jats:title> <jats:list list-type="simple"> <jats:list-item> <jats:label>–</jats:label> <jats:p> Adoptive transfer of <jats:italic>Bcl11b</jats:italic> KO CD8 <jats:sup>+</jats:sup> TILs surpasses WT in tumor burden reduction </jats:p> </jats:list-item> <jats:list-item> <jats:label>–</jats:label> <jats:p> <jats:italic>Bcl11b</jats:italic> ablation reprograms TILs and impairs the progression to Ttex state </jats:p> </jats:list-item> <jats:list-item> <jats:label>–</jats:label> <jats:p> <jats:italic>Bcl11b</jats:italic> KO CD8 <jats:sup>+</jats:sup> T cells have elevated cytotoxicity and kill only Ag-MHCI targets </jats:p> </jats:list-item> <jats:list-item> <jats:label>–</jats:label> <jats:p> <jats:italic>BCL11B</jats:italic> deletion in nonresponder ACT-TIL improves cytolytic activity and elevates TCF1 </jats:p> </jats:list-item> </jats:list> </jats:sec> <jats:sec> <jats:title>GRAPHICAL ABSTRACT</jats:title> <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="742578v1_ufig1" position="float" orientation="portrait"/> </jats:fig> </jats:sec>