Newnes Hannah V, Armitage Jesse D, Buzzai Anthony C, de Jong Emma, Audsley Katherine M, Barnes Samantha A, Srinivasan Shamini, Serralha Michael, Fear Vanessa S, Guo Belinda B, Jones Matt E, Forrest Alistair R R, Foley Bree, Darcy Phil K, Beavis Paul A, Bosco Anthony, Waithman Jason
School of Biomedical Sciences, The University of Western Australia, Perth, Australia.
The Kids Research Institute Australia, The University of Western Australia, Perth, Australia.
Sci Adv. 2025 May 16;11(20):eadt3618. doi: 10.1126/sciadv.adt3618. Epub 2025 May 14.
Despite advances in immunotherapy, metastatic melanoma remains a considerable therapeutic challenge due to the complexity of the tumor microenvironment. Intratumoral type I interferon (IFN-I) has long been associated with improved clinical outcomes. However, several IFN-I subtypes can also paradoxically promote tumor growth in some contexts. We investigated this further by engineering murine B16 melanoma cells to overexpress various IFN-I subtypes, where a spectrum of outcomes was observed. Characterization of these tumors by RNA sequencing revealed a tumor immune phenotype, where potent IFN-I signaling concomitant with diminished type 2 inflammation failed to confer durable tumor control. T cell-mediated rejection of these tumors was restored by introducing interleukin-4 (IL-4) into the tumor microenvironment, either through ectopic expression or in a preclinical adoptive T cell therapy model. Collectively, our findings highlight the IFN-I/IL-4 axis in promoting antitumor immunity, which could be harnessed to target and stratify solid tumors that are nonresponsive to frontline therapies.
尽管免疫疗法取得了进展，但由于肿瘤微环境的复杂性，转移性黑色素瘤仍然是一个巨大的治疗挑战。肿瘤内的I型干扰素（IFN-I）长期以来一直与改善临床结果相关。然而，在某些情况下，几种IFN-I亚型也可能反常地促进肿瘤生长。我们通过对小鼠B16黑色素瘤细胞进行基因工程改造，使其过表达各种IFN-I亚型，进一步研究了这一现象，观察到了一系列不同的结果。通过RNA测序对这些肿瘤进行表征，揭示了一种肿瘤免疫表型，即强大的IFN-I信号与减弱的2型炎症同时存在，但未能实现持久的肿瘤控制。通过将白细胞介素-4（IL-4）引入肿瘤微环境，无论是通过异位表达还是在临床前过继性T细胞治疗模型中，T细胞介导的对这些肿瘤的排斥反应得以恢复。总的来说，我们的研究结果突出了IFN-I/IL-4轴在促进抗肿瘤免疫中的作用，这可用于针对对一线治疗无反应的实体瘤并进行分层治疗。
