MLLT6 maintains PD‐L1 expression and mediates tumor immune resistance. (15th October 2020)

• Record Type: Journal Article
• Authors: Sreevalsan, Sandeep; Döring, Marietta; Paszkowski‐Rogacz, Maciej; Brux, Melanie; Blanck, Carolina; Meyer, Marten; Momburg, Frank; Buchholz, Frank; Theis, Mirko
• Is Part Of: EMBO reports. Volume 21:Number 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-10-15
• Subjects: cancer -- CRISPR screen -- immune resistance -- MLLT6 -- PD‐L1; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202050155
• Languages: English
• ISSNs: 1469-221X

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 MLLT6 (AF17) is required for efficient PD‐L1 protein expression and cell surface presentation in cancer cells. MLLT6 depletion alleviates suppression of CD8 + cytotoxic T cell‐mediated cytolysis. Furthermore, cancer cells lacking MLLT6 exhibit impaired STAT1 signaling and are insensitive to interferon‐γ‐induced stimulation of IDO1, GBP5, CD74, and MHC class II genes. Collectively, our findings establish MLLT6 as a regulator of oncogenic and interferon‐γ‐associated immune resistance. Synopsis: Cancer cells subvert immune surveillance by harnessing signals from immune checkpoints. MLLT6 is a modulator of the checkpoint protein PD‐L1, and its inhibition reduces immune checkpoint activity and alleviates suppression of CD8 + T cells. The transcriptional regulator MLLT6 promotes the expression of the immune checkpoint protein PD‐L1 in cancer cells. MLLT6 depletion impairs interferon‐γ signaling and STAT1 activity, diminishing the expression of immune‐related genes. MLLT6 inhibition promotes T cell mediated cytotoxicity and increases the efficacy of immunotherapies. Abstract : Cancer cells subvert immune surveillance by harnessing signals from immune checkpoints. MLLT6 is a modulator of the checkpoint protein PD‐L1, and its inhibition reduces immune checkpoint activity and alleviates suppression of CD8 + T cells.