Inhibition of the DNA damage response phosphatase PPM1D reprograms neutrophils to enhance anti-tumor immune responses
Year: 2021
Type: article
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.
Source: Nature Communications
Authors: 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, Oleg N. Demidov
Institutions: Inserm, Université de Bourgogne, Centre de recherche Translationnelle en Médecine moléculaire, Institute of Cytology, National Cancer Institute, Center for Cancer Research, Sirius University of Science and Technology, Federal Almazov North-West Medical Research Centre, University of Pennsylvania, Université d'Orléans, Centre National de la Recherche Scientifique, Immunologie et Neurogénétique Expérimentales et Moléculaires, Centre Hospitalier Universitaire de Besançon, Centre Georges François Leclerc, National Institutes of Health
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,560
Funders: U.S. Department of Health and Human Services, Regeneron Pharmaceuticals, Institut National de la Santé et de la Recherche Médicale, Russian Foundation for Basic Research, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Russian Science Foundation, National Institutes of Health, University of California, Davis, European Regional Development Fund, National Human Genome Research Institute, National Cancer Institute, National Center for Research Resources, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Awards: G140197035, G1517117645, G2024429596, G2106384714, G2138768168, G2474386524, G2527777273, G2934504215, G2978461159, Production of Targeted Null Mutations for 10,000 Genes in C57BL/6 ES Cells, G3466852870, G3965605844, High-throughput targeted mutagenesis of mouse stem cell lines, G4907197303, G5867801419, G6357487177, G676817753, G8542607633, G9000037257, G9000224493
OpenAlex ID: W3168969719