van Ravensteijn Stefan G, Amir Avital L, Tauriello Daniele V F, van Herpen Carla M L, Boers-Sonderen Marye J, Wesseling Yvonne J W, van Brussel Anne G C, Keizer Diederick M, Verheul Henk M W, Bol Kalijn F
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
Clin Exp Immunol. 2025 Jan 21;219(1). doi: 10.1093/cei/uxae108.
Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance.
The activity of 8 signaling pathways (TGF-β, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-β pathway activation was conducted by determining levels of phosphorylated SMAD2.
The mean TGF-β PAS of responders vs non-responders was 53.9 vs 56.8 (P = 0.265). No significant relation with progression-free survival was detected for TGF-β activity (P = 0.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P = 0.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P = 0.033) and worse progression-free survival (HR 1-1.1, P = 0.012).
TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival.
免疫检查点抑制（ICI）在黑色素瘤治疗中疗效显著，但部分患者存在内在抗性。转化生长因子-β（TGF-β）信号通路活性可能通过阻止T细胞进入肿瘤微环境导致免疫逃逸，从而在这种抗性中发挥作用。我们研究了TGF-β信号转导通路活性与晚期黑色素瘤ICI治疗抗性之间的关联。此外，还分析了其他信号通路活性，以更好地了解它们在ICI抗性中的潜在作用。
分析了晚期黑色素瘤患者肿瘤组织中8种信号通路（TGF-β、刺猬信号通路、丝裂原活化蛋白激酶（MAPK）、雄激素受体（AR）、Notch信号通路、磷脂酰肌醇-3激酶（PI3K）、Janus激酶/信号转导子和转录激活子1-2（JAK/STAT1-2）以及核因子κB（NFkB））的活性。在34例患者（19例无反应者和15例反应者）中，探索通路活性评分（PAS）与生存及ICI反应的相关性。通过测定磷酸化SMAD2水平，采用另一种独立方法研究TGF-β通路激活的预测价值。
反应者与无反应者的平均TGF-β PAS分别为53.9和56.8（P = 0.265）。未检测到TGF-β活性与无进展生存期之间存在显著相关性（P = 0.078）。未发现pSMAD2染色与治疗反应或生存之间存在关联。相比之下，反应者与无反应者的刺猬信号通路评分分别为35.7和41.6（P = 0.038）。高刺猬信号通路PAS是ICI抗性的唯一显著预测指标（比值比0.88，P = 0.033），且与较差的无进展生存期相关（风险比1 - 1.1，P = 0.012）。
TGF-β通路激活与晚期黑色素瘤患者对ICI的治疗反应或生存无显著相关性。刺猬信号通路PAS被确定为一种可能与治疗反应和生存均相关的生物标志物。
