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

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. We performed single-cell RNA sequencing on colorectal cancer patients with liver metastasis and obtained CD45+ cells from 101 samples including blood, mesenteric lymph nodes, matched primary and metastasis tumors and adjacent tissues.