ESMO Immuno-Oncology 2025 | CRISPR screening reveals MED16 as a novel immunotherapy target
Dimitrios Garyfallos, PhD, University College London, London, UK, explores findings from in vivo CRISPR/Cas9 screening that uncovered MED16 as a tumour-intrinsic regulator of anti-tumour immunity. Loss of this transcriptional mediator enhanced immune-mediated tumour rejection across preclinical models, and was driven by increased effector CD8+ T-cell infiltration and modulation of interferon pathways. This interview took place at 2025 European Society for Medical Oncology (ESMO) Immuno-Oncology Congress in London, UK.
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Transcript
Yeah, sure. So this project started with a screen and an attempt to use functional genomics to interrogate the genome of the cancer cell. So CRISPR-Cas9 is a powerful technology that allowed us to deactivate different genes across the entirety of the tumor cell genome. These tumor cells with the different genetic deletions were then injected into mice so that they could interact with the mouse immune system...
Yeah, sure. So this project started with a screen and an attempt to use functional genomics to interrogate the genome of the cancer cell. So CRISPR-Cas9 is a powerful technology that allowed us to deactivate different genes across the entirety of the tumor cell genome. These tumor cells with the different genetic deletions were then injected into mice so that they could interact with the mouse immune system. What we’re really interested in were the cancer genes that when you knock them out, the tumor cells would lose their ability to evade immune responses. So you knock out such a gene and the immune system recognizes the tumor cell more readily and attacks it. So this is a great target for immunotherapy. Through our studies, we identified such a gene called the mediator complex subunit 16 or MED16. So this is a member of a really big and important protein complex called the mediator and is effectively involved in the regulation of every protein-coding gene. Our work has revealed how the deactivation of this gene in the tumor cell leads to changes within the tumor cell itself and a robust anti-tumor immune response. And we’re very excited about harnessing those findings and designing immunotherapies and understanding more about how it works. What you would observe is that when you do such a screen, you have the capacity to interrogate the entirety of the tumor cell genome. So that gives you the opportunity of finding interactions that normally you wouldn’t notice due to the complexity of this experiment, what it allows you to focus on. When we identified this gene, initially, not many things were known about it. In the context of cancer cell immunology, at least, there were some studies in yeast, some studies in plants even. And what we did find is that this gene regulates the amount of transcription that happens in a cell in general, but also more specifically how the interferon pathways are regulated, specifically type 1, type 2 interferons. And what we suspect so far is that this gene actually makes the tumor cells more sensitive to interferon signaling, which makes them more interactive, more seen, more visible to the immune system, which then identifies the cancer and mounts a robust anti-tumor response.
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