High-Throughput Screening, CRISPR & Immunotherapy - The Sidi Chen Lab at Yale School of Medicine

Why It Matters

By turning genome‑wide CRISPR screens into actionable drug targets, the Chen lab accelerates the creation of novel immunotherapies, potentially transforming treatment options for patients with refractory cancers.

Key Takeaways

• CRISPR enables genome-wide screens of immune cell regulators.
• Unbiased high-throughput screens identify novel therapeutic gene targets.
• Three therapeutic strategies: target discovery, cell-based gene editing, systemic gene-editing therapy.
• Editing “undruggable” genes creates new immunotherapy avenues for patients.
• Translating screen hits into small molecules or antibodies accelerates drug pipelines.

Summary

The Sidi Chen laboratory at Yale School of Medicine is leveraging high‑throughput CRISPR screening to map every gene that influences immune‑cell behavior in cancer settings. By perturbing the full complement of ~20,000 human genes in vivo, the team seeks to pinpoint genetic levers that can be harnessed for next‑generation immunotherapies.

The approach yields three distinct therapeutic pathways: first, using screen hits to discover novel targets that can be attacked with conventional modalities such as small‑molecule inhibitors or monoclonal antibodies; second, directly editing “undruggable” genes within patient‑derived cells to create engineered cellular therapeutics; and third, delivering the gene‑editing machinery systemically as a gene‑therapy platform that reprograms the immune system in situ.

Chen emphasizes the “gene editing for, of, and as immunotherapy” paradigm, describing the shotgun, unbiased screens as a “shotgun approach” that narrows thousands of candidates to a manageable set of high‑impact genes. Examples include genes that modulate T‑cell exhaustion and checkpoints previously considered inaccessible to drug development.

The implications are profound: biotech firms can accelerate target validation, reduce reliance on serendipitous discovery, and open therapeutic avenues for cancers resistant to existing checkpoint inhibitors. Ultimately, this strategy promises to expand the immunotherapy arsenal and shorten the timeline from gene discovery to clinical candidate.

Original Description

For more information on Sidi Chen or #YaleSchoolOfMedicine, visit: https://medicine.yale.edu/profile/sidi-chen and https://sidichenlab.org.

The Sidi Chen Lab seeks a global understanding of the molecular factors controlling cancer progression and anti-tumor immunity. Towards this end, we utilize a diverse set of modern tools including high-throughput screening, in vivo CRISPR genome editing, animal models, synthetic biology, and bioinformatics. Our goal is to uncover novel insights in cancer and develop them into the next generation of therapeutics.

0:00 The Sidi Chen Lab

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