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A combinatorial transcription factor screening platform for immune cell reprogramming [scRNA-seq]

ABSTRACT: Direct reprogramming of immune cells holds promise for immunotherapy but is constrained by limited knowledge of transcription factor (TF) networks. Here, we developed REPROcode, a combinatorial single-cell screening platform to identify TF combinations for immune cell reprogramming. We first validated REPROcode by inducing Type-1 Conventional Dendritic Cells (cDC1) with multiplexed sets of 9, 22, and 42 factors. With cDC1-enriched TFs, REPROcode enabled identification of optimal TF stoichiometry, fidelity enhancers, and regulators of cDC1 states. We then constructed an arrayed lentiviral library of 408 barcoded immune TFs to explore broader reprogramming capacity. Screening 48 TFs enriched in dendritic cell subsets yielded myeloid and lymphoid phenotypes and enabled the construction of a TF hierarchy map to guide immune reprogramming. Finally, we validated REPROcode’s discovery power by inducing Natural Killer (NK)-like cells. This study deepens our understanding of immune transcriptional control and provides a versatile toolbox for engineering immune cells to advance immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298471 | GEO | 2026/01/14

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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A combinatorial transcription factor screening platform for immune cell reprogramming [scRNA-seq]

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