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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249361 | GEO | 2024/01/23

REPOSITORIES: GEO

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Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.

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

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