@article{c7b4c3e1081a419eac233aca10c97a60,
title = "Cancer-Specific Loss of p53 Leads to a Modulation of Myeloid and T Cell Responses",
abstract = "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. TP53 is one of the most frequently mutated genes in cancer; however, its significance in controlling tumor-immune crosstalk is not fully understood. Blagih et al. highlight a key role for tumor-associated loss of p53, a common oncogenic event, in regulating myeloid and T cell responses.",
keywords = "Kras, myeloid cells, p53, T cell response, tumor",
author = "Julianna Blagih and Fabio Zani and Probir Chakravarty and Marc Hennequart and Steven Pilley and Sebastijan Hobor and Hock, {Andreas K.} and Walton, {Josephine B.} and Morton, {Jennifer P.} and Eva Gronroos and Susan Mason and Ming Yang and Iain McNeish and Charles Swanton and Karen Blyth and Vousden, {Karen H.}",
note = "Funding Information: We would like to thank the histology team at the Beatson Institute for Cancer Research and the animal facilities at the Francis Crick and Beatson Institutes. J.B. was funded by a Canadian Institute of Health Research (CIHR) postdoctoral grant. J.B.W. was funded by the Marsh Rivkin Center for Ovarian Cancer . S.H. and E.G. were funded by a European Research Council (ERC) THESEUS grant. We would like to acknowledge and thank the Pear lab and Castro lab for donating their plasmids to Addgene ( Pear et al., 1998; Yang et al., 2010 ). This work was funded by Cancer Research UK grants C596/A10419 and C596/A26855 , and supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001557 ), the UK Medical Research Council ( FC001557 ), and the Wellcome Trust ( FC001557 ), and the CRUK Beatson Institute , which receives its core funding from Cancer Research UK grant C596/A17196 . C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001169 and FC001202 ), the UK Medical Research Council ( FC001169 and FC001202 ), and the Wellcome Trust ( FC001169 and FC001202 ). C.S. is funded by Cancer Research UK (TRACERx, PEACE, and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence , the Rosetrees Trust, NovoNordisk Foundation ( ID16584 ), and the Breast Cancer Research Foundation (BCRF). This research is supported by a Stand Up To Cancer ‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team translational research grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research , the Scientific Partner of Stand Up To Cancer. C.S. receives funding from the ERC under the European Union{\textquoteright}s Seventh Framework Programme ( FP7/2007-2013 ) consolidator grant ( FP7-THESEUS-617844 ); European Commission ITN (FP7-PloidyNet 607722); an ERC advanced grant (PROTEUS) from the ERC under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement 835297 ); and Chromavision from the European Union {\textquoteright}s Horizon 2020 research and innovation program (grant agreement 665233 ). Funding Information: We would like to thank the histology team at the Beatson Institute for Cancer Research and the animal facilities at the Francis Crick and Beatson Institutes. J.B. was funded by a Canadian Institute of Health Research (CIHR) postdoctoral grant. J.B.W. was funded by the Marsh Rivkin Center for Ovarian Cancer. S.H. and E.G. were funded by a European Research Council (ERC) THESEUS grant. We would like to acknowledge and thank the Pear lab and Castro lab for donating their plasmids to Addgene (Pear et al. 1998; Yang et al. 2010). This work was funded by Cancer Research UK grants C596/A10419 and C596/A26855, and supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001557), the UK Medical Research Council (FC001557), and the Wellcome Trust (FC001557), and the CRUK Beatson Institute, which receives its core funding from Cancer Research UK grant C596/A17196. C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169 and FC001202), the UK Medical Research Council (FC001169 and FC001202), and the Wellcome Trust (FC001169 and FC001202). C.S. is funded by Cancer Research UK (TRACERx, PEACE, and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, the Rosetrees Trust, NovoNordisk Foundation (ID16584), and the Breast Cancer Research Foundation (BCRF). This research is supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team translational research grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of Stand Up To Cancer. C.S. receives funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013) consolidator grant (FP7-THESEUS-617844); European Commission ITN (FP7-PloidyNet 607722); an ERC advanced grant (PROTEUS) from the ERC under the European Union's Horizon 2020 research and innovation program (grant agreement 835297); and Chromavision from the European Union's Horizon 2020 research and innovation program (grant agreement 665233). The study was conceived and designed by J.B. F.Z. S.H. E.G. M.H. K.B. and K.H.V. Investigations were conducted by J.B. F.Z. M.H. S.P. A.H. S.H. J.B.W. S.M. M.Y. and J.P.M. Bioinformatics analysis was carried out by P.C. The manuscript was written by J.B. F.Z. and K.H.V. and all authors contributed to the review of the paper. K.H.V. is on the board of directors and shareholder of Bristol Myers Squibb, a shareholder of GRAIL, and on the science advisory board of PMV Pharma, RAZE Therapeutics, and Ludwig Cancer. She is a co-founder and consultant of Faeth Therapeutics, funded by Khosla Ventures. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of patent application WO/2017/144877. C.S. receives grant support from Pfizer, AstraZeneca, BMS, Roche-Ventana, and Boehringer-Ingelheim; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, and the Sarah Cannon Research Institute; is an advisor for Dynamo Therapeutics; is a shareholder of Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options in and is co-founder of Achilles Therapeutics. I.A.M. is on the advisory boards for Clovis Oncology, Tesaro, AstraZeneca, Roche, and Carrick Therapeutics and is in receipt of research funding from AstraZeneca. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2020",
month = jan,
day = "14",
doi = "10.1016/j.celrep.2019.12.028",
language = "English",
volume = "30",
pages = "481--496.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}