MLLT6 maintains PD-L1 expression and mediates tumor immune resistance
Sandeep Sreevalsan1, Marietta Döring1, Maciej Paszkowski-Rogacz2
1National Center for Tumor Diseases (NCT/UCC) Dresden, German Cancer Research Center (DKFZ), University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
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.
Insights
Researchers identified MLLT6 as a key regulator of tumor immune resistance. Depleting MLLT6 enhances anti-tumor immunity by reducing PD-L1 expression and improving T cell responses.
Area of Science:
- Immunology
- Cancer Biology
- Genetics
Background:
- Tumor cells evade immune surveillance through immune checkpoints like PD-L1.
- While PD-L1 inhibition shows promise, it's not universally effective, necessitating new target discovery.
- Understanding the genetic basis of tumor immune evasion is crucial for developing novel cancer therapies.
Purpose of the Study:
- To identify genes that enable cancer cells to evade immune attack using a CRISPR/Cas9 screen.
- To elucidate the role of MLLT6 in regulating tumor immune resistance.
Main Methods:
- Conducted a CRISPR/Cas9 screen in human cancer cells to identify immune evasion genes.
- Assessed the impact of MLLT6 depletion on PD-L1 expression and immune cell activity.
- Analyzed STAT1 signaling and interferon-γ-induced gene expression in MLLT6-deficient cells.
Main Results:
- Identified MLLT6 as essential for PD-L1 protein expression and cell surface presentation.
- MLLT6 depletion enhanced CD8+ cytotoxic T cell-mediated killing of tumor cells.
- Loss of MLLT6 impaired STAT1 signaling and interferon-γ-stimulated gene induction (IDO1, GBP5, CD74, MHC class II).
Conclusions:
- MLLT6 is a critical regulator of tumor immune resistance.
- MLLT6 influences both PD-L1-mediated immune suppression and interferon-γ signaling pathways.
- MLLT6 represents a potential therapeutic target for enhancing anti-tumor immunity.
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