Base editing screens map mutations affecting interferon-γ signaling in cancer
- PMID: 36669486
- PMCID: PMC9942875
- DOI: 10.1016/j.ccell.2022.12.009
Base editing screens map mutations affecting interferon-γ signaling in cancer
Abstract
Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ signaling pathway cause immunological disorders, hematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer; however, the function of most clinically observed variants remains unknown. Here, we systematically investigate the genetic determinants of IFN-γ response in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations, including causal variants in hematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumor organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumor-reactive T cells. We identify more than 300 predicted missense mutations altering IFN-γ pathway activity, generating a valuable resource for interpreting gene variant function.
Keywords: IFN-γ signaling; base editing; cancer genetics; cancer immunotherapy; drug resistance; functional genomics; gene editing; interferon gamma; variants of uncertain significance.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests M.J.G. has received research grants from AstraZeneca, GlaxoSmithKline, and Astex Pharmaceuticals, and is a founder and advisor for Mosaic Therapeutics.
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