Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression

Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed “senescence surveillance.” However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2+ myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2+ myeloid cells, and CCR2 ablation caused outgrowth of HCC. In contrast, HCC cells block the maturation of recruited myeloid precursors, which, through NK cell inhibition, promote growth of murine HCC and worsen the prognosis and survival of human HCC patients. Thus, while senescent hepatocyte-secreted chemokines suppress liver cancer initiation, they may accelerate the growth of fully established HCC. [Display omitted] •The CCL2-CCR2 axis is necessary for clearance of pre-cancerous senescent hepatocytes•Absence of the CCL2-CCR2 axis leads to HCC outgrowth from senescent hepatocytes•Peritumoral tissue senescence accelerates growth of HCC in mice and humans•Senescence-recruited CCR2+ myeloid cells enhance HCC growth by NK cell inhibition Eggert et al. show that CCL2 is secreted from oncogene-induced senescent hepatocytes to recruit CCR2+ immature myeloid cells (iMC). These iMC differentiate into macrophages that clear pre-malignant senescent cells, but iMC promote growth of established hepatocellular carcinoma through NK cell inhibition.