Faculty, Staff and Student Publications

Publication Date

9-5-2024

Journal

Cell

DOI

10.1016/j.cell.2024.06.013

PMID

38971151

Abstract

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (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 (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) 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 class 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.

Keywords

Female, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Humans, T-Lymphocytes, Regulatory, Animals, Mice, Neoadjuvant Therapy, Tumor Microenvironment, Piperidines, Indazoles, Homologous Recombination, CD8-Positive T-Lymphocytes, Cell Line, Tumor, CCR8, HGSOC, HRD, PARP inhibitor, chemotherapy, effector Treg, neoadjuvant therapy, single-cell transcriptomics, tumor microenvironment, tumor-reactive T cell

Published Open-Access

yes

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