MLLT6 maintains PD‐L1 expression and mediates tumor immune resistance
Sandeep Sreevalsan, Marietta Döring, Maciej Paszkowski‐Rogacz, Melanie Brux, Carolina Blanck, Marten Meyer, Frank Momburg, Frank Buchholz, Mirko Theis
Abstract
Abstract Tumor cells subvert immune surveillance by harnessing signals from immune checkpoints to acquire immune resistance. The protein PD ‐L1 is an important component in this process, and inhibition of PD ‐L1 elicits durable anti‐tumor responses in a broad spectrum of cancers. However, immune checkpoint inhibition that target known pathways is not universally effective. A better understanding of the genetic repertoire underlying these processes is necessary to expand our knowledge in tumor immunity and to facilitate identification of alternative targets. Here, we present a CRISPR /Cas9 screen in human cancer cells to identify genes that confer tumors with the ability to evade the cytotoxic effects of the immune system. We show that the transcriptional regulator MLLT 6 ( AF 17) is required for efficient PD ‐L1 protein expression and cell surface presentation in cancer cells. MLLT 6 depletion alleviates suppression of CD 8 + cytotoxic T cell‐mediated cytolysis. Furthermore, cancer cells lacking MLLT 6 exhibit impaired STAT 1 signaling and are insensitive to interferon‐γ‐induced stimulation of IDO 1 , GBP 5 , CD 74, and MHC class II genes. Collectively, our findings establish MLLT 6 as a regulator of oncogenic and interferon‐γ‐associated immune resistance.