Using autochthonous pancreas and lung cancer mouse models, Blagih et al. showed that tumor-specific p53 loss increased tumor cell secretion of myeloid cell-attracting/differentiating cytokines and tumor infiltration of T cell-suppressive macrophages. p53-null tumor cell lines conditioned myeloid cells to reduce T helper 1 and killer activity. Growth of p53-null tumor transplants was enhanced in immunocompetent versus athymic hosts, and targeted inhibition demonstrated a key inhibitory role for Tregs. p53 mutations were enriched in patients with pancreatic cancer with tumor-promoting, high myeloid-derived suppressor cell signatures.
Contributed by Paula Hochman
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.
Author Info: (1) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (2) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (3) The Francis Crick Institute, 1 Midland
Author Info: (1) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (2) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (3) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (4) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (5) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (6) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (7) Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK; Discovery Sciences, R&D BioPharmaceuticals, AstraZeneca, Cambridge CB4 0WG, UK. (8) Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK. (9) Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK. (10) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (11) Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK. (12) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (13) Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK; Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK. (14) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (15) Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK. (16) The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: karen.vousden@crick.ac.uk.
