# CRISPR screens in the context of immune selection identify CHD1 and MAP3K7 as mediators of cancer immunotherapy resistance

## TL;DR

The paper identifies CHD1 and MAP3K7 as genes that influence cancer cells' resistance to immunotherapy, suggesting they could be used as biomarkers for treatment response.

## Contribution

The study introduces a novel CRISPR-based approach to identify genes mediating cancer immunotherapy resistance in the context of immune selection.

## Key findings

- Loss of CHD1 and MAP3K7 increases cancer cell sensitivity to IFN-γ and T cell-mediated killing.
- Reduced CHD1/MAP3K7 expression correlates with better immunotherapy response in mice and patients.
- CRISPR screens reveal cytokine-induced cancer dependencies relevant to immune checkpoint blockade.

## 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+ 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.

•CRISPR-Cas9 co-culture screens with patient-derived tumoroids and autologous T cells•Large-scale map of cytokine-induced cancer dependencies•CHD1 and MAP3K7 (TAK1) loss enhances sensitivity to IFN-γ•Low tumor expression of CHD1/MAP3K7 is linked to improved ICB response in mice and patients.

CRISPR-Cas9 co-culture screens with patient-derived tumoroids and autologous T cells

Large-scale map of cytokine-induced cancer dependencies

CHD1 and MAP3K7 (TAK1) loss enhances sensitivity to IFN-γ

Low tumor expression of CHD1/MAP3K7 is linked to improved ICB response in mice and patients.

Immunotherapies only provide benefit for a subset of individuals with cancer, highlighting the need for biomarkers of response. Using whole-genome CRISPR-Cas9 screens, Watterson et al. map genetic dependencies in the context of four cytokines and tumor-reactive T cells, identifying CHD1 and MAP3K7 as mediators of resistance to IFN-γ-induced cancer cell death.