Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Affiliations

• Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• R&A Data, New York, NY, USA
• Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA
• Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
• Department of Systems Biology, Harvard Medical School, Boston, MA, USA
• Ludwig Center at Harvard, Boston, MA, USA

PMID:  39481380  DOI: 10.1016/j.cell.2024.10.006

Abstract

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.

卵巢癌对免疫疗法的抗性与以巨噬细胞为主的免疫抑制性肿瘤微环境（TME）密切相关，而肿瘤内异质性的形成机制尚不清楚。为了识别影响卵巢癌免疫的调节因子，我们采用了一种空间功能基因组筛选技术（Perturb-map），重点研究与肿瘤-巨噬细胞通讯相关的受体和配体。结果显示，Perturb-map重现了肿瘤异质性，并发现白介素-4（IL-4）促进了对抗PD-1疗法的抵抗。研究发现，卵巢癌细胞是IL-4的主要来源，通过控制巨噬细胞形成免疫抑制性TME。IL-4的缺失并未被附近的IL-4表达克隆所弥补，揭示了短距离调节对TME组成的影响，从而决定肿瘤演变。我们的研究表明，肿瘤来源的细胞因子和趋化因子的局部表达改变可以导致异质性的TME形成，进而创造出免疫丰富和免疫排斥的微环境，推动克隆选择和免疫疗法的抵抗。此外，研究还显示，靶向IL-4信号通路有潜力增强卵巢癌对免疫疗法的反应。

关键词：IL4，REGN1103，29F.1A12，免疫治疗，靶向治疗，肿瘤，卵巢癌，流式抗体，佰乐博，佰乐博生物