Abstract Aim: Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce the immune-mediated clearance of these senescent cells, preventing malignant transformation and tumor initiation; a process termed ‘senescence surveillance’. However, senescent hepatocytes can give rise to hepatocellular carcinomas (HCC), if additional oncogenic mutations, e.g. p53 mutation, abrogate the senescence program. We set out to investigate the effect of senescent cell secreted cytokines on growth of neighboring liver tumor cells. Experimental procedure: To induce senescence in mouse livers, we hydrodynamically injected a transposon system, which encodes for either oncogenic Nras (NrasG12V) or an effector loop mutant (NrasG12V/D38A) that is incapable of signaling to downstream pathways, into C57BL/6 or CCR2-/- mice. To achieve tumor development in senescent livers, hepatocellular carcinoma cells were intrasplenically injected into mice, which expressed either NrasG12V or NrasG12V/D38A in the liver. Hepatic immune cell infiltrates were analyzed using flow cytometry and immunohistochemistry. Immunosuppressive ability of CD11b+Gr1+ myeloid cells was analyzed in vitro after fluorescence-activated cell sorting. Furthermore, peritumor tissue of 226 HCC patients was hierarchical clustered based on the expression of 35 senescence-associated genes. Senescence-associated gene signature was then compared with CCL2 expression and survival. Results: Senescent hepatocytes promoted growth of hepatocellular carcinoma cells through accumulation of immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ cells inhibited T cell proliferation via an iNOS-dependent mechanism. Immunosuppressive myeloid cell accumulation as well as tumor growth promotion was abrogated, when senescence was induced in livers of CCR2 knockout mice, indicating a pivotal role for CCL2 in creating a tumor promoting immune environment. Finally, gene expression analysis in patients with hepatocellular carcinoma confirmed the association of senescence-induced CCL2 expression in peritumor tissue and poor prognosis. Conclusion: Senescent hepatocytes not only induce an inflammatory response that leads to their own clearance, preventing tumor initiation, but surprisingly also induce the accumulation of immunosuppressive myeloid cells that promote growth of neighboring hepatocellular carcinomas. Citation Format: Tobias Eggert, Juling Ji, Lars Zender, Xin Wei Wang, Tim F. Greten. Senescent hepatocytes secrete CCL2 to accelerate liver cancer growth via accumulation of immunosuppressive myeloid cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 360. doi:10.1158/1538-7445.AM2015-360