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Inhibition of the DNA damage response phosphatase PPM1D reprograms neutrophils to enhance anti-tumor immune responses

Author

Listed:
  • Burhan Uyanik

    (University of Burgundy Franche-Comté)

  • Anastasia R. Goloudina

    (University of Burgundy Franche-Comté
    Institute of Cytology, RAS)

  • Aamir Akbarali

    (Center for Center Research, National Cancer Institute)

  • Bogdan B. Grigorash

    (Institute of Cytology, RAS
    NTU Sirius)

  • Alexey V. Petukhov

    (NTU Sirius
    Almazov National Medical Research Centre)

  • Sunil Singhal

    (University of Pennsylvania)

  • Evgeniy Eruslanov

    (University of Pennsylvania)

  • Jeanne Chaloyard

    (University of Burgundy Franche-Comté)

  • Lisa Lagorgette

    (University of Burgundy Franche-Comté)

  • Tarik Hadi

    (University of Burgundy Franche-Comté)

  • Ekaterina V. Baidyuk

    (Institute of Cytology, RAS)

  • Hiroyasu Sakai

    (Center for Center Research, National Cancer Institute)

  • Lino Tessarollo

    (Center for Cancer Research, National Cancer Institute)

  • Bernhard Ryffel

    (University of Orléans, CNRS, UMRP735)

  • Sharlyn J. Mazur

    (Center for Center Research, National Cancer Institute)

  • Frederic Lirussi

    (University of Burgundy Franche-Comté
    University hospital of Besançon (CHU), 2 Boulevard Fleming)

  • Carmen Garrido

    (University of Burgundy Franche-Comté
    Georges François Leclerc Center)

  • Ettore Appella

    (Center for Center Research, National Cancer Institute)

  • Oleg N. Demidov

    (University of Burgundy Franche-Comté
    Institute of Cytology, RAS
    NTU Sirius)

Abstract

PPM1D/Wip1 is a negative regulator of the tumor suppressor p53 and is overexpressed in several human solid tumors. Recent reports associate gain-of-function mutations of PPM1D in immune cells with worse outcomes for several human cancers. Here we show that mice with genetic knockout of Ppm1d or with conditional knockout of Ppm1d in the hematopoietic system, in myeloid cells, or in neutrophils all display significantly reduced growth of syngeneic melanoma or lung carcinoma tumors. Ppm1d knockout neutrophils infiltrate tumors extensively. Chemical inhibition of Wip1 in human or mouse neutrophils increases anti-tumor phenotypes, p53-dependent expression of co-stimulatory ligands, and proliferation of co-cultured cytotoxic T cells. These results suggest that inhibition of Wip1 in neutrophils enhances immune anti-tumor responses.

Suggested Citation

  • Burhan Uyanik & Anastasia R. Goloudina & Aamir Akbarali & Bogdan B. Grigorash & Alexey V. Petukhov & Sunil Singhal & Evgeniy Eruslanov & Jeanne Chaloyard & Lisa Lagorgette & Tarik Hadi & Ekaterina V. , 2021. "Inhibition of the DNA damage response phosphatase PPM1D reprograms neutrophils to enhance anti-tumor immune responses," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23330-6
    DOI: 10.1038/s41467-021-23330-6
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