556 Transcription factor Zfx regulates tumor’s evasion to T cell killing in immunotherapy

<h3>Background</h3> A large fraction of patients with cancer exhibit an intrinsic or acquired resistance to immunotherapies that aim at boosting T cell responses against tumor cells. <h3>Methods</h3> To better understand resistance mechanisms in tumor cells, we used CRISPR-Cas9 whole-genome editing to identify modified tumor cells that are resistant to T cell killing. <h3>Results</h3> Among the top hits, we identified the transcription factor zinc-finger protein X-linked (Zfx). Zfx knockout tumor cells are resistant to T cell killing both <i>in vitro</i> and <i>in vivo</i>. Mechanistically we showed that Zfx regulates expression of genes involved in apoptosis pathways and Caspase-3 is one of the central components regulated by Zfx. In addition, ZFX expression is decreased in several human cancer tissues compared to healthy tissues. Female kidney renal clear cell carcinoma (KIRC) patients with high ZFX expression showed longer survival compared to patients with low ZFX expression. <h3>Conclusions</h3> Our results demonstrate a novel resistant mechanism in tumor cells and suggest that targeting tumor cell intrinsic resistance genes in combination with immune therapies could benefit cancer patients.