Ovarian cancer-derived IL-4 promotes immunotherapy resistance

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2024-10-30 DOI:10.1016/j.cell.2024.10.006

Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. 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 Merad, Alessia Baccarini, Brian D. Brown

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引用次数: 0

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.

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卵巢癌衍生的IL-4可增强免疫疗法的抗药性

卵巢癌对免疫疗法有抵抗力，这是受以巨噬细胞为主的免疫抑制肿瘤微环境（TME）的影响。抗药性还受到瘤内异质性的影响，而对这种异质性的发展还知之甚少。为了确定卵巢癌免疫的调控因子，我们采用了空间功能基因组学筛选（Perturb-map），重点是假设参与肿瘤-巨噬细胞交流的受体/配体。Perturb-map再现了肿瘤的异质性，并揭示了白细胞介素-4（IL-4）可促进对抗PD-1的抵抗。我们发现卵巢癌细胞是IL-4的主要来源，IL-4通过巨噬细胞的控制引导免疫抑制性TME的形成。IL-4的损失不会被附近表达IL-4的克隆所补偿，这揭示了TME组成的短程调控决定了肿瘤的演变。我们的研究表明，癌症衍生细胞因子/凝血因子的局部表达改变可产生异质性TME，这些细胞因子/凝血因子可建立免疫富集区和免疫排斥区，从而驱动克隆选择和免疫治疗抵抗。这些研究还证明了靶向 IL-4 信号增强卵巢癌对免疫疗法反应的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.