Turpin Rita, Peltonen Karita, Rannikko Jenna H, Liu Ruixian, Kumari Anita N, Nicorici Daniel, Lee Moon Hee, Mutka Minna, Kovanen Panu E, Niinikoski Laura, Meretoja Tuomo, Mattson Johanna, Järvinen Petrus, Lahdensuo Kanerva, Järvinen Riikka, Tornberg Sara, Mirtti Tuomas, Boström Pia, Koskivuo Ilkka, Thotakura Anil, Pouwels Jeroen, Hollmén Maija, Mustjoki Satu, Klefström Juha
Cancer Cell Circuitry Laboratory, Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland.
MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland.
Oncoimmunology. 2025 Dec;14(1):2466305. doi: 10.1080/2162402X.2025.2466305. Epub 2025 Feb 17.
Tumor-resident immune cells play a crucial role in eliciting anti-tumor immunity and immunomodulatory drug responses, yet these functions have been difficult to study without tractable models of the tumor immune microenvironment (TIME). Patient-derived models contain authentic resident immune cells and therefore, could provide new mechanistic insights into how the TIME responds to tumor or immune cell-directed therapies. Here, we assessed the reproducibility and robustness of immunomodulatory drug responses across two different models of breast cancer TIME and one of renal cell carcinoma. These independently developed TIME models were treated with a panel of clinically relevant immunomodulators, revealing remarkably similar changes in gene expression and cytokine profiles among the three models in response to T cell activation and STING-agonism, while still preserving individual patient-specific response patterns. Moreover, we found two common core signatures of adaptive or innate immune responses present across all three models and both types of cancer, potentially serving as benchmarks for drug-induced immune activation in models of the TIME. The robust reproducibility of immunomodulatory drug responses observed across diverse models of the TIME underscores the significance of human patient-derived models in elucidating the complexities of anti-tumor immunity and therapeutic interventions.
肿瘤驻留免疫细胞在引发抗肿瘤免疫和免疫调节药物反应中发挥着关键作用，但如果没有易于处理的肿瘤免疫微环境（TIME）模型，这些功能很难进行研究。患者来源的模型包含真实的驻留免疫细胞，因此，可以为TIME如何响应肿瘤或免疫细胞导向疗法提供新的机制见解。在这里，我们评估了两种不同的乳腺癌TIME模型和一种肾细胞癌模型中免疫调节药物反应的可重复性和稳健性。这些独立开发的TIME模型用一组临床相关的免疫调节剂进行处理，结果显示，在三种模型中，响应T细胞激活和STING激动剂时，基因表达和细胞因子谱的变化非常相似，同时仍保留个体患者特异性的反应模式。此外，我们在所有三种模型以及两种癌症类型中都发现了适应性或先天性免疫反应的两个共同核心特征，这可能作为TIME模型中药物诱导免疫激活的基准。在不同的TIME模型中观察到的免疫调节药物反应的强大可重复性强调了患者来源模型在阐明抗肿瘤免疫和治疗干预复杂性方面的重要性。
