生物
免疫疗法
卵巢癌
癌症
癌症研究
抗性(生态学)
癌症免疫疗法
免疫学
遗传学
生态学
作者
Gürkan Mollaoglu,Alexander Tepper,Chiara Falcomatà,Hunter Potak,Luisanna Pia,Angelo Amabile,Jaime Mateus-Tique,Noam Rabinovich,Matthew D. Park,Nelson M. LaMarche,Rachel Brody,Lindsay Browning,Jia‐Ren Lin,Dmitriy Zamarin,Peter K. Sorger,Sandro Santagata,Miriam Mérad,Alessia Baccarini,Brian D. Brown
出处
期刊:Cell
[Elsevier]
日期:2024-10-01
标识
DOI:10.1016/j.cell.2024.10.006
摘要
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.
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