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Single-cell analyses reveal phenotypic linkage between colorectal cancer and liver metastasis

ABSTRACT: The tumor microenvironment (TME) is intrinsically associated with clinical responses of immunotherapy, but it remains opaque how cancer cells and host tissues differentially influence its immune composition. Here, we performed systematic single-cell analyses for autologous clinical samples from liver metastasized colorectal cancer patients, as well as non-metastatic primary liver and colon cancer patients to disentangle different factors shaping TME. By aligning CD45+ cells within metastatic tumors across different tissue types, we classified exhausted CD8+ T (Tex) cells and activated Tregs as M-type, whose phenotypes were associated with the malignancy, while NK and MAIT cells were defined as N-type, whose phenotypes were associated with the niche. Significant TCR sharing existed between Tex cells in primary and metastatic tumors as well as peripheral non-exhausted T cells, implicating the presence of common peripheral precursors that were independently developed into Tex. For myeloid cells, DC3s and SPP1+ tumor-associated macrophages were classified as M-type, and the latter were also predominantly present in liver metastasis, indicating its pro-metastasis roles. Our analysis bridges the immune phenotypes of primary and metastatic tumors, paving ways to better understand the tumor-specific contexture and to target key components in the metastasis process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164522 | GEO | 2022/02/12

REPOSITORIES: GEO

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Project description:Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

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Single-cell analyses reveal phenotypic linkage between colorectal cancer and liver metastasis

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