Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma
Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma
复制标题
单细胞 RNA 测序揭示恶性 T 细胞和骨髓细胞之间的通讯，促进皮肤 T 细胞淋巴瘤的肿瘤生长和免疫抑制
DOI：
10.1016/j.canlet.2022.215972
复制
发表时间：
2022-10-20
期刊：
影响因子：
9.7
通讯作者：
Feng, Jifeng
中科院分区：
文献类型：
--
作者：
Du, Yuxin;Cai, Yun;Feng, Jifeng
皮肤T细胞淋巴瘤（CTCL）的特点是恶性T细胞在皮肤中积聚。然而，由于瘤内异质性高和复杂的肿瘤微环境（TME），晚期 CTCL 的病理生理学仍然难以捉摸，治疗选择也受到限制。通过比较晚期 CTCL 患者和健康对照 (HC) 的单细胞 RNA 序列 (scRNA-seq) 数据，我们发现 CTCL 具有更高的 T/NK 和骨髓细胞富集度。 T细胞亚群（CXCR3（+）、GNLY（+）、CREM+和MKI67（+）T细胞）具有高增殖、干性和拷贝数变异（CNV）水平，导致CTCL的恶性。此外，CCL13（+）单核细胞/巨噬细胞和LAMP3（+）cDC细胞被富集，并通过与恶性T细胞（例如CD47-SIRPA、MIF-CD74和CCR1-CCL18）的抑制性相互作用介导免疫抑制。值得注意的是，在 CTCL 的恶性细胞和骨髓细胞中均观察到 S100A9 及其受体 TLR4 的表达升高，以及下游 Toll 样受体和 NF-κ B 通路的激活。细胞共培养实验进一步证实恶性CTCL细胞和巨噬细胞之间的相互作用通过S100A9上调和NF-kb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-kappa B 通路失活，抑制 CTCL 肿瘤细胞的生长，并引发细胞凋亡。总的来说，我们的研究揭示了恶性 T 细胞和骨髓细胞之间相互作用介导的免疫抑制 TME 的景观，并为晚期 CTCL 患者提供了新的靶点和潜在的治疗策略
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-kappa B 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-kappa B 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