Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma

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

Automated summary

The study revealed the landscape of an immunosuppressive tumor microenvironment mediated by interactions between malignant T cells and myeloid cells, and provided novel targets and potential treatment strategies for advanced CTCL patients.