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.