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 Petukhov, Sunil Singhal, Evgeniy Eruslanov, Jeanne Chaloyard, Lisa Lagorgette, Tarik Hadi, E. V. Baidyuk, Hiroyasu Sakai, Lino Tessarollo, Bernhard Ryffel, Sharlyn J. Mazur, Frédéric Lirussi, Carmen Garrido, Ettore Appella, Oleg N. Demidov
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.