Yang Jiekun, Wang Cassia, Fu Doris, Ho Li-Lun, Galani Kyriakitsa, Chen Lee, Gonzalez Jose, Fu Jolene, Huang Amy Y, Frederick Dennie T, He Liang, Asnani Mukta, Tacke Rahul, Robitschek Emily J, Yadav Sandeep K, Deng Wentao, Burke Kelly P, Sharova Tatyana, Sullivan Ryan J, Weiss Sarah, Rai Kunal, Liu David, Boland Genevieve M, Kellis Manolis
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Commun. 2025 Sep 1;16(1):8151. doi: 10.1038/s41467-025-62878-5.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet most patients fail to achieve durable responses. To better understand the tumor microenvironment (TME), we analyze single-cell RNA-seq (~189 K cells) from 36 metastatic melanoma samples, defining 14 cell types, 55 subtypes, and 15 transcriptional hallmarks of malignant cells. Correlations between cell subtype proportions reveal six distinct clusters, with a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC) linked to naive T and B cells. Importantly, mregDC abundance predicts progression-free survival (PFS) with ICIs and other therapies, especially when combined with the TCF7 + /- CD8 T cell ratio. Analysis of an independent cohort (n = 318) validates mregDC as a predictive biomarker for anti-CTLA-4 plus anti-PD-1 therapies. Further characterization of mregDCs versus conventional dendritic cells (cDC1/cDC2) highlights their unique transcriptional, epigenetic (single-nucleus ATAC-seq data for cDCs from 14 matched samples), and interaction profiles, offering new insights for improving immunotherapy response and guiding future combination treatments.
免疫检查点抑制剂（ICIs）彻底改变了癌症治疗方式，但大多数患者未能实现持久缓解。为了更好地了解肿瘤微环境（TME），我们分析了来自36个转移性黑色素瘤样本的单细胞RNA测序数据（约18.9万个细胞），定义了14种细胞类型、55个亚型以及恶性细胞的15个转录特征。细胞亚型比例之间的相关性揭示了六个不同的簇，其中一种富含免疫调节分子的成熟树突状细胞亚型（mregDC）与幼稚T细胞和B细胞相关。重要的是，mregDC丰度可预测ICI及其他疗法的无进展生存期（PFS），尤其是与TCF7 + / - CD8 T细胞比率相结合时。对一个独立队列（n = 318）的分析验证了mregDC作为抗CTLA-4加抗PD-1疗法的预测生物标志物。mregDC与传统树突状细胞（cDC1/cDC2）的进一步特征比较突出了它们独特的转录、表观遗传（来自14个匹配样本的cDC的单核ATAC测序数据）和相互作用图谱，为改善免疫治疗反应和指导未来联合治疗提供了新的见解。
