Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Cell Cycle. 2023 Jan;22(1):57-72. doi: 10.1080/15384101.2022.2109105. Epub 2022 Aug 3.
Considering the determining role of TGFβ signaling in the tumor microenvironment (TME) on immune evasion, the inhibition of signaling is expected to enhance the therapeutic efficacy of immunotherapies, especially immune checkpoint blockade (ICB), which is confirmed in preclinical data. However, successive failures in clinical translation occur at the initial stage. To provide a better understanding of TGFβ signaling within the TME and its relation to the individual immunological status, we performed a pan-cancer analysis comparing the activation of TGFβ pathway among different TMEs based on multi-omics data. Compared with non-inflamed tumors, increased TGFβ signaling activity appeared in four non-cancer cell types within TME in inflamed tumors. Significant correlations were revealed between TGFβ signaling and reliable biomarkers for ICB therapy, as well as between TGFβ signaling and HPV status. Our findings contribute to explain the inconsistency between preclinical and clinical research, and are crucial to optimizing upcoming clinical trial design and improving patient stratification for personalized prediction.
鉴于 TGFβ 信号在肿瘤微环境 (TME) 中对免疫逃逸的决定性作用，抑制信号有望增强免疫疗法的疗效，特别是免疫检查点阻断 (ICB)，这在临床前数据中得到了证实。然而，在临床转化的初始阶段，接连失败。为了更好地理解 TGFβ 信号在 TME 中的作用及其与个体免疫状态的关系，我们基于多组学数据，对不同 TME 中 TGFβ 途径的激活进行了泛癌症分析。与非炎症性肿瘤相比，炎症性肿瘤中 TGFβ 信号活性增加出现在 TME 中的四种非癌细胞类型中。TGFβ 信号与 ICB 治疗的可靠生物标志物之间以及 TGFβ 信号与 HPV 状态之间存在显著相关性。我们的研究结果有助于解释临床前和临床研究之间的不一致性，对于优化未来的临床试验设计和改善患者分层以进行个性化预测至关重要。
