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

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. Baidyuk, Hiroyasu Sakai, Lino Tessarollo, Bernhard Ryffel, Sharlyn J. Mazur, Frederic Lirussi, Carmen Garrido (), Ettore Appella () and Oleg N. Demidov ()
Additional contact information
Burhan Uyanik: University of Burgundy Franche-Comté
Anastasia R. Goloudina: University of Burgundy Franche-Comté
Aamir Akbarali: Center for Center Research, National Cancer Institute
Bogdan B. Grigorash: Institute of Cytology, RAS
Alexey V. Petukhov: NTU Sirius
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
Carmen Garrido: University of Burgundy Franche-Comté
Ettore Appella: Center for Center Research, National Cancer Institute
Oleg N. Demidov: University of Burgundy Franche-Comté

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23330-6

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