Ovarian cancer-derived IL-4 promotes immunotherapy resistance
Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.
Journal
CellAuthors
Funding
Identifying Genetic Drivers of the Immunosuppressive Tumor Microenvironment in Lung CancerAdvancing technologies for the collection and analysis of high dimensional immunoprofiles and tumor imagesVisual Analytics for Exploration and Hypothesis Generation Using Highly MultiplexedSpatial Data of Tissues and TumorsMolecular, Cellular, and Tissue Characterization UnitSpatial functional genomics to identify regulators of the tumor microenvironment and cancer immunityConduits: Mount Sinai Health System Translational Science HubInvestigating Macrophage Molecular and Functional Diversity in Tumor ImmunityDevelopment of a platform for spatial functional genomicsCOVID and Translational Science supercomputer (CATS)Deciphering the molecular control of intratumoral dendritic cellsType 2 immunity: a primitive response to epithelial injury that shapes bone marrow and lung myeloid crosstalkAdmin Core