Single-cell transcriptomics reveals the role of antigen presentation in liver metastatic breast cancer

Liver metastasis (LM) is the primary cause of cancer-related mortality in late-stage breast cancer (BC) patients. However, the complexity and diversity of the tumor microenvironment (TME) of LM have not been fully understood. Here we report an in-depth analysis of the transcriptional landscape of liver metastases of 11 patients with secondary hepatic carcinoma at single-cell resolution. Our study reveals that terminally exhausted CD4+ and dysfunctional CD8+ T cells were enriched in metastatic tumor along with low antigen presentation. We also found macrophages were associated with the infiltration profile of CD4+ T cells, while FCN3+ macrophages, type 1 conventional dendritic cells (cDC1) and LAMP3+ DC regulated T cell functions, probably via antigen processing and presentation. MHC expression in FCN3+ macrophage, cDC1 and LAMP3+ DC was reduced in LM compared to those in normal tissues and primary tumor of BC. Dysfunction of antigen presentation in these cells is linked to a worse prognosis in breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC) cohorts and identifies potentially targetable immune inhibitory pathways in secondary hepatic carcinoma. Thus, our results show a cellular diversity of TME in BC-LM, providing valuable insights into the role of tumor infiltrating T cells in liver metastatic cancers. Overall design: Single-cell RNA-seq profiling for liver metastases of 11 patients with secondary hepatic carcinoma: 6 cases of breast cancer (BC), 2 cases of nasopharyngeal carcinoma (NPC), 2 cases of thyroid carcinoma (THCA), 1 case of cervical carcinoma (CESC), and adjacent nonmalignant tissues (used as normal control).