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Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [10x scRNA-seq]

ABSTRACT: Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [10x scRNA-seq]

PROVIDER: PRJNA922525 | ENA |

REPOSITORIES: ENA

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Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors

Project description:Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors

| PRJNA922522 | ENA

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [10x scRNA-seq]

Project description:Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to PARP inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T-cell receptor profiles, along with validatory multimodal datasets from > 100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTreg) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC-II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

2024-07-08 | GSE222556 | GEO

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [Singleron scRNA-seq]

Project description:Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [Singleron scRNA-seq]

| PRJNA1123701 | ENA

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [bulk TCR-seq]

Project description:Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [bulk TCR-seq]

| PRJNA922526 | ENA

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [Singleron scTCR-seq]

Project description:Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [Singleron scTCR-seq]

| PRJNA922527 | ENA

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [Singleron scTCR-seq]

2024-07-08 | GSE222555 | GEO

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [bulk TCR-seq]

2024-07-08 | GSE222554 | GEO

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors [Singleron scRNA-seq]

2024-07-08 | GSE269793 | GEO

Neoadjuvant PARPi or Chemotherapy in Ovarian Cancer Informs Targeting Effector Treg Cells for Homologous-Recombination-Deficient Tumors

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-07-05 | GSE222557 | GEO

ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (RNA-seq)

Project description:The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair mechanisms and the abundance of lesions that trap PARP enzymes on chromatin. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR based screen, we identify the PAR-binding Snf2-like ATPase, ALC1 as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of BRCA mutant cells and enhanced their sensitivity to PARPi by up to 250-fold, while overcoming several known resistance mechanisms. ALC1 loss was not epistatic to other repair pathways that execute the PARPi response. Instead, ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of repair factors. This resulted in an accumulation of replication associated DNA damage and a reliance on HR. These findings establish PAR-dependent chromatin remodeling as a mechanistically distinct aspect of PARPi responses, implicating ALC1 inhibition as a new approach to overcome therapeutic resistance in HR-deficient cancers.

2020-12-02 | GSE149104 | GEO

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