Base editing screens map mutations affecting interferon-γ signaling in cancer.
Cancer Cell
; 41(2): 288-303.e6, 2023 02 13.
Article
in En
| MEDLINE
| ID: mdl-36669486
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Hematologic Neoplasms
/
Neoplasms
Limits:
Humans
Language:
En
Journal:
Cancer Cell
Journal subject:
NEOPLASIAS
Year:
2023
Type:
Article
Affiliation country:
United kingdom