Ovarian cancer has high clonal heterogeneity and an immunosuppressed tumor microenvironment (TME) that contribute to resistance to immunotherapy. Research now published in Cell finds that IL-4 produced by cancer cells promotes resistance to immune checkpoint blockade (ICB). To identify extracellular factors that influence ICB resistance and ovarian tumor growth, the authors assessed the impact of specific receptors and ligands involved in cancer–macrophage interactions using a spatial functional genomics approach called Perturb-map. They constructed a Pro-Code/CRISPR library targeting the selected genes, each encoding a unique protein barcode, and introduced the library into mouse ovarian cancer cells and implant them into immunocompetent mice. Cancer-derived extracellular factors such as MIF, CCL3, CCL7 and PLAUR were shown to influence tumor growth. To identify genes involved in the poor ICB response, the authors treated the mice with anti-PD1 after injection of their generated tumor cells. They found that cancer cell-derived IL-4 influences tumor sensitivity to ICB by promoting the formation of an immunosuppressive TME via its effects on tumor macrophages. These findings offer a potential therapeutic treatment for ICB-resistant tumors.

Original reference: Cell https://doi.org/10.1016/j.cell.2024.10.006 (2024)