Du Yuxin, Cai Yun, Lv Yan, Zhang Lishen, Yang Hao, Liu Quanzhong, Hong Ming, Teng Yue, Tang Weiyan, Ma Rong, Wu Jianqiu, Wu Jianzhong, Wang Qianghu, Chen Hongshan, Li Kening, Feng Jifeng
The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, China.
Center for Global Health, School of Public Health, Nanjing Medical University, 211166, Nanjing, Jiangsu, China; Department of Bioinformatics, Nanjing Medical University, 211166, Nanjing, China.
Cancer Lett. 2022 Dec 28;551:215972. doi: 10.1016/j.canlet.2022.215972. Epub 2022 Oct 17.
Cutaneous T cell lymphoma (CTCL) is characterized by the accumulation of malignant T cells in the skin. However, advanced CTCL pathophysiology remains elusive and therapeutic options are limited due to the high intratumoral heterogeneity and complicated tumor microenvironment (TME). By comparing the single-cell RNA-seq (scRNA-seq) data from advanced CTCL patients and healthy controls (HCs), we showed that CTCL had a higher enrichment of T/NK and myeloid cells. Subpopulations of T cells (CXCR3, GNLY, CREM, and MKI67 T cells), with high proliferation, stemness, and copy number variation (CNV) levels, contribute to the malignancy of CTCL. Besides, CCL13 monocytes/macrophages and LAMP3 cDC cells were enriched and mediated the immunosuppression via inhibitory interactions with malignant T cells, such as CD47-SIRPA, MIF-CD74, and CCR1-CCL18. Notably, elevated expressions of S100A9 and its receptor TLR4, as well as the activation of downstream toll-like receptor and NF-κB pathway were observed in both malignant cells and myeloid cells in CTCL. Cell co-culture experiments further confirmed that the interaction between malignant CTCL cells and macrophages contributed to tumor growth via S100A9 upregulation and NF-kb activation. Our results showed that blocking the S100A9-TLR4 interaction using tasquinimod could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells, and trigger cell apoptosis. Collectively, our study revealed a landscape of immunosuppressive TME mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.
皮肤T细胞淋巴瘤（CTCL）的特征是恶性T细胞在皮肤中积聚。然而，由于肿瘤内高度异质性和复杂的肿瘤微环境（TME），晚期CTCL的病理生理学仍不清楚，治疗选择也有限。通过比较晚期CTCL患者和健康对照（HC）的单细胞RNA测序（scRNA-seq）数据，我们发现CTCL中T/NK细胞和髓系细胞的富集程度更高。具有高增殖、干性和拷贝数变异（CNV）水平的T细胞亚群（CXCR3、GNLY、CREM和MKI67 T细胞）促成了CTCL的恶性肿瘤形成。此外，CCL13单核细胞/巨噬细胞和LAMP3 cDC细胞富集，并通过与恶性T细胞的抑制性相互作用介导免疫抑制，如CD47-SIRPA、MIF-CD74和CCR1-CCL18。值得注意的是，在CTCL的恶性细胞和髓系细胞中均观察到S100A9及其受体TLR4的表达升高，以及下游Toll样受体和NF-κB通路的激活。细胞共培养实验进一步证实，恶性CTCL细胞与巨噬细胞之间的相互作用通过S100A9上调和NF-κB激活促进肿瘤生长。我们的结果表明，使用他喹莫德阻断S100A9-TLR4相互作用可以使NF-κB通路失活，抑制CTCL肿瘤细胞的生长，并触发细胞凋亡。总的来说，我们的研究揭示了由恶性T细胞和髓系细胞之间的相互作用介导的免疫抑制性TME景观，并为晚期CTCL患者提供了新的靶点和潜在的治疗策略。
