{
  "abstract": "Background High-grade serous carcinoma (HGSC) of the ovary acquires chemoresistance through diverse cancer cell-intrinsic and cell-extrinsic mechanisms, culminating in treatment-refractory intraperitoneal metastasis. Previous work suggests that chemotherapy induces immunological changes in the tumor microenvironment (TME). However, experimental evidence for how such chemotherapy-induced TME remodeling modulates the response to ongoing chemotherapy remains poorly documented in HGSC.Methods We analyzed paired pre-chemotherapy and post-chemotherapy HGSC bulk transcriptomic and single-cell RNA sequencing (scRNA-seq) datasets to identify chemotherapy-induced tumor-extrinsic factors and their cellular sources in the TME. To test causality, we used chemoresistant, homologous recombination-proficient murine metastatic HGSC models with deficiencies in the interleukin 1 beta (IL1β) pathway (IL1β–interleukin 1 receptor type 1 (IL1R1) axis). Flow cytometry and scRNA-seq of omental tumors were used to define cellular interactions. Contributions of neutrophils and neutrophil extracellular traps (NETs) were assessed by antibody-mediated depletion and immunofluorescence. Direct effects of IL1β and NETs on cancer cell chemosensitivity were tested in vitro. Finally, paired pre-chemotherapy and post-chemotherapy omental HGSC specimens from patients were analyzed for neutrophil infiltration and NET formation.Results In HGSC datasets, post-chemotherapy tumors exhibited increased IL1β expression with myeloid cells identified as the primary source. In chemoresistant murine models, chemotherapy increased neutrophils and NETs in omentum tumors in wild-type mice. These increases were abrogated in IL1β-deficient mice, which showed a shift toward an effector-like CD8 + T-cell state and improved tumor control. Neutrophil depletion in wild-type mice recapitulated the chemosensitive phenotype of IL1β-deficient mice. In vitro, IL1β did not alter cancer cell-intrinsic chemosensitivity, whereas NETs reduced the chemosensitivity of cancer cells. Furthermore, scRNA-seq and flow cytometry revealed that IL1R1 was predominantly expressed by tumor-associated fibroblasts. Consistently, IL1R1-deficient mice exhibited increased chemosensitivity, with decreased neutrophil accumulation and increased IFNγ+TNF+CD8+ T cells. Additionally, we found that chemotherapy upregulated the neutrophil chemoattractant C-X-C motif chemokine ligand 2 (CXCL2), and disruption of the IL1β–IL1R1 axis decreased CXCL2 levels in tumor-associated fibroblasts. Finally, residual human HGSC tumors after chemotherapy showed increased neutrophils and a trend toward increased NETs.Conclusions We demonstrate that chemotherapy-induced IL1β-dependent neutrophil accumulation drives chemoresistance in HGSC. This study provides experimental evidence that chemotherapy-induced inflammation contributes to chemoresistance and highlights the potential of targeting this pathway to overcome chemoresistance in HGSC.",
  "authors": [
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA",
        "Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"
      ],
      "name": "Taito Miyamoto"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Yujie Ye"
    },
    {
      "affiliations": [
        "Immunology Graduate Group, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Marlaine M Soliman"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA",
        "Cancer Biology Graduate Program, Saint Joseph's University, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Bryan S Manning"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Brennah Murphy"
    },
    {
      "affiliations": [
        "Undergraduate Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Linna Zhu"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Chunlei Shao"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Gauri Mirji"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Moeko Minakuchi"
    },
    {
      "affiliations": [
        "Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"
      ],
      "name": "Kohei Hamada"
    },
    {
      "affiliations": [
        "Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"
      ],
      "name": "Rin Mizuno"
    },
    {
      "affiliations": [
        "Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"
      ],
      "name": "Mana Taki"
    },
    {
      "affiliations": [
        "Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"
      ],
      "name": "Koji Yamanoi"
    },
    {
      "affiliations": [
        "Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"
      ],
      "name": "Ryusuke Murakami"
    },
    {
      "affiliations": [
        "Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"
      ],
      "name": "Masaki Mandai"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Ying Ye"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Jayamanna Wickramasinghe"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Yulia Nefedova"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Rahul Shinde"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Andrew Kossenkov"
    },
    {
      "affiliations": [
        "Wistar Institute, Philadelphia, Pennsylvania, USA",
        "Immunology Graduate Group, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Nan Zhang"
    }
  ],
  "title": "Chemotherapy induces an IL1β-dependent neutrophil recruitment and activation that promote chemoresistance in metastatic ovarian cancer",
  "uid": "c3cd74d8-dd18-5b35-bd4c-56334dfbe083"
}