美国西奈山伊坎医学院Brian D. Brown等研究人员合作发现，卵巢癌来源的IL-4促进免疫治疗抵抗。相关论文于2024年10月30日在线发表在《细胞》杂志上。
为了识别卵巢癌免疫的调节因子，研究人员采用了一种空间功能基因组筛选方法（Perturb-map），重点关注假设与肿瘤-巨噬细胞通信相关的受体/配体。Perturb-map重现了肿瘤异质性，并揭示白介素-4（IL-4）促进对抗PD-1的抵抗。
研究人员发现卵巢癌细胞是IL-4的主要来源，它通过控制巨噬细胞来引导免疫抑制性肿瘤微环境（TME）的形成。IL-4的缺失并未被附近的IL-4表达克隆所补偿，揭示了短程调节TME组成的机制决定了肿瘤的演变。
该研究表明，异质性TME可以源自癌症来源的细胞因子/趋化因子的局部表达改变，这些因子建立了富含免疫细胞和免疫排斥的邻域，进而驱动克隆选择和免疫治疗抵抗。该研究还显示，靶向IL-4信号通路有可能增强卵巢癌对免疫治疗的反应。
据悉，卵巢癌对免疫治疗具有抵抗性，这受到以巨噬细胞为主的免疫抑制TME的影响。抗药性还受肿瘤内异质性的影响，而其发展的机制尚不清楚。
附：英文原文
Title: Ovarian cancer-derived IL-4 promotes immunotherapy resistance
Author: 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
Issue&Volume: 2024-10-30
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.
DOI: 10.1016/j.cell.2024.10.006
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01154-1