The Francis Crick Institute
1-s2.0-S221112471931678X-main.pdf (3.47 MB)

Cancer-specific loss of p53 leads to a modulation of myeloid and T cell responses.

Download (3.47 MB)
journal contribution
posted on 2020-01-23, 13:40 authored by Julianna Blagih, Fabio Zani, Probir Chakravarty, Marc Hennequart, Steven Pilley, Sebastijan Hobor, Andreas K Hock, Josephine B Walton, Jennifer P Morton, Eva Gronroos, Susan Mason, Ming Yang, Iain McNeish, Charles Swanton, Karen Blyth, Karen H Vousden
Loss of p53 function contributes to the development of many cancers. While cell-autonomous consequences of p53 mutation have been studied extensively, the role of p53 in regulating the anti-tumor immune response is still poorly understood. Here, we show that loss of p53 in cancer cells modulates the tumor-immune landscape to circumvent immune destruction. Deletion of p53 promotes the recruitment and instruction of suppressive myeloid CD11b+ cells, in part through increased expression of CXCR3/CCR2-associated chemokines and macrophage colony-stimulating factor (M-CSF), and attenuates the CD4+ T helper 1 (Th1) and CD8+ T cell responses in vivo. p53-null tumors also show an accumulation of suppressive regulatory T (Treg) cells. Finally, we show that two key drivers of tumorigenesis, activation of KRAS and deletion of p53, cooperate to promote immune tolerance.


Crick (Grant ID: 10557, Grant title: Vousden FC001557) Crick (Grant ID: 10169, Grant title: Swanton FC001169) Crick (Grant ID: 10202, Grant title: Van Loo FC001202) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS)