Huang Yuhong, Liu Han, Liu Xuena, Li Nan, Bai Han, Guo Chenyang, Xu Tian, Zhu Lei, Liu Chao, Xiao Jing
Department of Oral Pathology, School of Stomatology, Dalian Medical University, Dalian, China.
Dalian Key Laboratory of Basic Research in Oral Medicine, School of Stomatology, Dalian Medical University, Dalian, China.
Front Genet. 2022 May 27;13:820065. doi: 10.3389/fgene.2022.820065. eCollection 2022.
The immune checkpoint blockade (ICB) with anti-programmed cell death protein 1(PD-1) on HNSCC is not as effective as on other tumors. In this study, we try to find out the key factors in the heterogeneous tumor-associated monocyte/macrophage (TAMM) that could regulate immune responses and predict the validity of ICB on HNSCC. To explore the correlation of the TAMM heterogeneity with the immune properties and prognosis of HNSCC, we established the differentiation trajectory of TAMM by analyzing the single-cell RNA-seq data of HNSCC, by which the HNSCC patients were divided into different sub-populations. Then, we exploited the topology of the network to screen out the genes critical for immune hot phenotype of HNSCC, as well as their roles in TAMM differentiation, tumor immune cycle, and progression. Finally, these key genes were used to construct a neural net model via deep-learning framework to predict the validity of treatment with anti-PD-1/PDL-1 According to the differentiation trajectory, the genes involved in TAMM differentiation were categorized into early and later groups. Then, the early group genes divided the HNSCC patients into sub-populations with more detailed immune properties. Through network topology, CXCL9, 10, 11, and CLL5 related to TAMM differentiation in the TME were identified as the key genes initiating and maintaining the immune hot phenotype in HNSCC by remarkably strengthening immune responses and infiltration. Genome wide, CASP8 mutations were found to be key to triggering immune responses in the immune hot phenotype. On the other hand, in the immune cold phenotype, the evident changes in CNV resulted in immune evasion by disrupting immune balance. Finally, based on the framework of CXCL9-11, CLL5, CD8, CD4 T cells, and Macrophage M1, the neural network model could predict the validity of PD-1/PDL-1 therapy with 75% of AUC in the test cohort. We concluded that the CXCL9, 10,11, and CCL5 mediated TAMM differentiation and constructed immune hot phenotype of HNSCC. Since they positively regulated immune cells and immune cycle in HNSCC, the CXCL9-11 and CCL5 could be used to predict the effects of anti-PD-1/PDL-1 therapy on HNSCC.
抗程序性细胞死亡蛋白1（PD-1）的免疫检查点阻断（ICB）疗法对头颈部鳞状细胞癌（HNSCC）的疗效不如对其他肿瘤显著。在本研究中，我们试图找出肿瘤相关单核细胞/巨噬细胞（TAMM）异质性中的关键因子，这些因子可调节免疫反应并预测ICB疗法对HNSCC的有效性。为了探究TAMM异质性与HNSCC免疫特性及预后的相关性，我们通过分析HNSCC的单细胞RNA测序数据建立了TAMM的分化轨迹，并据此将HNSCC患者分为不同亚群。然后，我们利用网络拓扑结构筛选出对HNSCC免疫热表型至关重要的基因，以及它们在TAMM分化、肿瘤免疫循环和进展中的作用。最后，通过深度学习框架，利用这些关键基因构建神经网络模型，以预测抗PD-1/PDL-1治疗的有效性。根据分化轨迹，将参与TAMM分化的基因分为早期和晚期两组。早期组基因进一步将HNSCC患者分为具有更详细免疫特性的亚群。通过网络拓扑分析，发现肿瘤微环境（TME）中与TAMM分化相关的CXCL9、10、11和CCL5基因是启动和维持HNSCC免疫热表型的关键基因，它们通过显著增强免疫反应和免疫细胞浸润来实现这一作用。全基因组分析发现，半胱天冬酶8（CASP8）突变是免疫热表型中触发免疫反应的关键因素。另一方面，在免疫冷表型中，拷贝数变异（CNV）的明显变化通过破坏免疫平衡导致免疫逃逸。最后，基于CXCL9-11、CCL5、CD8、CD4 T细胞和巨噬细胞M1构建的神经网络模型在测试队列中预测PD-1/PDL-1治疗有效性的曲线下面积（AUC）为75%。我们得出结论，CXCL9、10、11和CCL5介导TAMM分化并构建了HNSCC的免疫热表型。由于它们在HNSCC中对免疫细胞和免疫循环具有正向调节作用，CXCL9-11和CCL5可用于预测抗PD-1/PDL-1疗法对HNSCC的疗效。
