Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma. (28th December 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cancer letters. Volume 551(2022)
• Publication Date: 2022-12-28
• Subjects: Cutaneous T cell lymphoma -- Intratumoral heterogeneity -- Tumor microenvironment -- Myeloid cells -- S100A9; CTCL Cutaneous T-cell lymphoma -- MF mycosis fungoides -- SS sezary syndrome -- RR refractory or relapsed -- scRNA-seq single-cell RNA sequencing -- TME tumor microenvironment -- HCs healthy controls -- CNVs copy number variations -- PI Propidium iodide -- PVDF Polyvinylidene fluoride -- IF Immunofluorescence -- GEO Gene Expression Omnibus -- PCA principal component analysis -- PCs principal components -- UMAP uniform manifold approximation and projection -- SNN shared nearest neighbor -- REG reversed graph embedding -- DEGs differentially expressed genes -- TF transcription factors -- KEGG Kyoto Encyclopedia of Genes and Genomes -- GO Gene ontology -- ENKTL extranodal T/NK cell lymphoma -- cDC conventional dendritic cells -- OXPHOS oxidative phosphorylation -- TCA tricarboxylic acid -- ICIs immune checkpoint inhibitors -- MPN myeloproliferative neoplasms -- MDSC myeloid-derived suppressor cells; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215972
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: CTCL has a higher enrichment of T and myeloid cells compared with healthy controls (HCs). T cell subpopulations with high proliferation, stemness and CNV levels, contribute to the malignancy of CTCL. CCL13+ mono/macrophages and LAMP3+ cDC cells interact with malignant T cells to shape the immunosuppression of CTCL. NF-κB pathway induced by S100A9 and TLR4 interaction is activated in both malignant and myeloid cells in CTCL. Blocking the S100A9-TLR4 interaction could inactivate the NF-κB pathway and inhibit the growth of CTCL tumor cells.