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Chemotherapeutic Induction of Single-Stranded DNA Accumulation Sensitizes Triple-Negative Breast Cancer to Immunotherapy [scRNA-seq]

ABSTRACT: Despite the widespread adoption of chemo-immunotherapy in triple-negative breast cancer (TNBC), how cytotoxic chemotherapy engages antitumor immunity remains poorly defined. Here, we identify cytosolic single-stranded DNA (ssDNA) accumulation as the mechanistic bridge linking genotoxic stress to immune activation. By integrating in vivo TREX1-deficiency transcriptional signatures, we show that ssDNA-driven immunostimulatory programs—rather than TREX1 expression—robustly predict clinical response to chemo-immunotherapy across independent TNBC cohorts. Through a chemotherapeutic screen, we identify LP-184, an acylfulvene-derived alkylating agent in clinical development, as a potent pharmacologic inducer of cytosolic ssDNA and type I interferon signaling. LP-184 enhances antigen presentation, reduces M2-like tumor-suppressive macrophages, and promotes CD8⁺ T-cell priming, thereby synergizing with anti-PD-1 therapy in vivo. These findings redefine the interface between DNA damage and immune activation, establishing ssDNA-driven immune programs as both a predictive biomarker and a therapeutic axis for next-generation chemo-immunotherapy design.

ORGANISM(S): Mus musculus

PROVIDER: GSE311488 | GEO | 2026/06/20

REPOSITORIES: GEO

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Chemotherapeutic Induction of Single-Stranded DNA Accumulation Sensitizes Triple-Negative Breast Cancer to Immunotherapy

Project description:Despite the widespread adoption of chemo-immunotherapy in triple-negative breast cancer (TNBC), how cytotoxic chemotherapy engages antitumor immunity remains poorly defined. Here, we identify cytosolic single-stranded DNA (ssDNA) accumulation as the mechanistic bridge linking genotoxic stress to immune activation. By integrating in vivo TREX1-deficiency transcriptional signatures, we show that ssDNA-driven immunostimulatory programs—rather than TREX1 expression—robustly predict clinical response to chemo-immunotherapy across independent TNBC cohorts. Through a chemotherapeutic screen, we identify LP-184, an acylfulvene-derived alkylating agent in clinical development, as a potent pharmacologic inducer of cytosolic ssDNA and type I interferon signaling. LP-184 enhances antigen presentation, reduces M2-like tumor-suppressive macrophages, and promotes CD8⁺ T-cell priming, thereby synergizing with anti-PD-1 therapy in vivo. These findings redefine the interface between DNA damage and immune activation, establishing ssDNA-driven immune programs as both a predictive biomarker and a therapeutic axis for next-generation chemo-immunotherapy design.

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Chemotherapeutic Induction of Single-Stranded DNA Accumulation Sensitizes Triple-Negative Breast Cancer to Immunotherapy [RNA-Seq]

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Project description:Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to Immune Checkpoint Blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING dependent Type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.

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ARID1A suppresses R-loop mediated STING-Type I Interferon pathway activation of anti-tumor immunity (ChIP-Seq)

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ARID1A suppresses R-loop mediated STING-Type I Interferon pathway activation of anti-tumor immunity (ATAC-Seq)

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Multi-omics profiling uncovers immune-molecular clusters with distinct chemo-immunotherapeutic vulnerabilities in a mouse model of triple-negative breast cancer

Project description:Background: Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited treatment options. Predicting patient response to chemo-immunotherapy remains challenging, highlighting the need for robust stratification strategies. Methods: We performed a multi-parametric analysis combining histological, genomic, transcriptomic, proteomic, and immune profiling in the immunocompetent MMTV-R26Met TNBC mouse model and compared outcomes with patient data from human TNBC cohorts and TNBC tumor microarray. To enable therapeutic testing and functional validation, we established syngeneic grafts from primary tumors and used them to evaluate combined chemotherapy (epirubicin) and anti-PD-1 immunotherapy. Results: Multi-parametric analysis of TNBC heterogeneity modeled by the MMTV-R26Met mice identified four distinct TNBC clusters, defined by unique intrinsic (molecular/genomic) and extrinsic (immune) features, which closely parallel patient subtypes, including rare metaplastic forms, and correlate with clinical outcomes. Both intrinsic and immune hallmarks of primary tumors were conserved across serial syngeneic transplantations, confirming the translational value of this preclinical platform. Treatment assessments indicated cluster-specific therapeutic vulnerabilities associated with molecular and immune traits. Specifically, whereas chemo-immunotherapy is beneficial to neutrophil-enriched tumors, immunotherapy alone appears to be more effective in macrophage-enriched tumors. Our findings indicate that TNBC treatment response is shaped by the interplay between tumor-intrinsic and immune features. Conclusion: Our study provides a robust preclinical platform for precision immuno-oncology, enabling stratification of TNBC patients for tailored onco-immunotherapies.

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A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease that often relapses following treatment with standard radiotherapies and cytotoxic chemotherapies. Combination therapies have potential for treating refractory metastatic TNBC. Here, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemo-immunotherapy for TNBC. The overexpression of an immune checkpoint transmembrane CD276 (also known as B7-H3) was associated with angiogenesis, metastasis, and immune tolerance, in over 60% of TNBC patients. Development of a monoclonal antibody (mAb) capable of targeting the extracellular domain of surface CD276 enabled delivery of payloads to tumors, and a platform was established for concurrent conjugation of a traditional cytotoxic payload and an immunoregulating toll-like receptor 7/8 agonist to the CD276 mAb. The DualADC effectively killed multiple TNBC subtypes, significantly enhanced immune functions in the tumor microenvironment, and reduced tumor burden by up to 90-100% in animal studies. Single-cell RNA-sequencing, multiplex cytokine analysis, and histology elucidated the impact of treatment on tumor cells and the immune landscape. This study suggests that the developed DualADC could represent a promising targeted chemo-immunotherapy for TNBC.

2024-08-21 | GSE274871 | GEO

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Project description:The DNA exonuclease TREX1 degrades endogenous cytosolic DNA. Cytosolic DNA triggers the cGAS/STING pathway which increases type I interferon. To investigate the physiological significance of TREX1 loss on in vivo tumor growth, we implanted control and TREX1-deficient CT26 tumor cells into immunocompetent BALB/c hosts.Tumor cells were collected 7 days after tumors reached around 200mm3.

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