CRISPR screens in the context of immune selection identify CHD1 and MAP3K7 as mediators of cancer immunotherapy resistance.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41564866.
- Also identified by DOI 10.1016/j.xcrm.2025.102565 and PMC identifier 12866162.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Cancer immunotherapy is only effective in a subset of patients, highlighting the need for effective biomarkers and combination therapies. Here, we systematically identify genetic determinants of cancer cell sensitivity to anti-tumor immunity by performing whole-genome CRISPR-Cas9 knockout screens in autologous tumoroid-T cell co-cultures, isogenic cancer cell models deficient in interferon signaling, and in the context of four cytokines. We discover that loss of CHD1 and MAP3K7 (encoding TAK1) potentiates the transcriptional response to IFN-γ, thereby creating an acquired vulnerability by sensitizing cancer cells to tumor-reactive T cells. Immune checkpoint blockade is more effective in a syngeneic mouse model of melanoma deficient in Chd1 and Map3k7 and is associated with elevated intra-tumoral CD8<sup>+</sup> T cell numbers and activation. CHD1 and MAP3K7 are recurrently mutated in cancer, and reduced expression in tumors correlates with response to immune checkpoint inhibitors in patients, nominating these genes as potential biomarkers of immunotherapy response.
Medical subject headings
- Immunotherapy
- MAP Kinase Kinase Kinases
- DNA Helicases
- CRISPR-Cas Systems
- DNA-Binding Proteins
- Drug Resistance, Neoplasm
- Neoplasms