Single tumor-initiating cells evade immune clearance by recruiting type II macrophages

Abstract

Tumor infiltrated type II (M2) macrophages promote tumorigenesis by suppressing immune clearance, promoting proliferation, and stimulating angiogenesis. Interestingly, macrophages were also found to enrich in small foci of altered hepatocytes containing liver tumor-initiating cells (TICs). However, whether and how TICs specifically recruit macrophages and the function of these macrophages in tumor initiation remain unknown due to technical difficulties. In this study, by generating genetically defined liver TICs, we demonstrate that TICs actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages (TICAMs) abolishes tumorigenesis in a manner dependent on the immune system. Mechanistically, activation of the Hippo pathway effector Yes-associated protein (YAP) underlies macrophage recruitment by TICs. These results demonstrate for the first time that macrophages play a decisive role in the survival of single TICs in vivo and provide a proof of principle for TIC elimination by targeting YAP or M2 macrophages.

Sequential adaptive changes in a c-Myc-driven model of hepatocellular carcinoma

“…Relevant to these findings is a recent report by Guo et al (88) who utilized a different murine HCC model induced by the hydrodynamic tail injection of mutant YAP. Although these animals do not develop tumors until 12-16 weeks, the homing of macrophages to YAP+ tumor-initiating hepatocytes could be detected as early as two days postinjection and well before the development of any discernible tumors.…”

Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

“…When Hippo signaling is inactivated, YAP/TAZ enter the nucleus, bind to the transcription factor TEADs, and induce gene transcription. Recently, the effects of the Hippo pathway components on tumor initiation and growth in the context of reciprocal interactions between tumor cells and host anti-tumor immune responses have emerged Guo et al, 2017;Kim et al, 2017;Zhang et al, 2017b). Previous studies have convincingly demonstrated the Hippo pathway as a suppressor signal for cellular transformation and tumorigenesis (Moroishi et al, 2015a).…”

A shortcut for early macrophage recruitment into tumors by activated oncogenes

“…However, the remarkable conclusion that can be drawn from the study by Guo et al (2017) is that even single tumor cells at the very beginning of tumorigenesis become able to evade immune clearance by recruiting macrophages, and this is due to the ability of specific activated oncogenes to directly attract these cells. Aside from its remarkable biological interest, this study is not devoid of potential medical implications, as it suggests that the interference with the activation of the Hippo pathway, in addition to its possible direct effects on parenchymal tumor cells, may unleash an efficient antitumor response.…”

“…It is therefore not surprising that this pathway is frequently deregulated in tumorigenesis. The study by Guo et al (2017) investigated the possibility that the Hippo pathway may be directly involved in the recruitment of macrophages to promote liver carcinogenesis and used experimental strategies to track the interplay between macrophages and tumor-initiating cells from the very beginning of the process.…”

“…Specifically, Guo et al (2017) used extensive genetic analyses, largely based on hydrodynamic tail vein injection (Chen and Calvisi 2014), which leads to plasmid uptake and integration in a fraction of hepatocytes. Stable expression of constitutively active (phosphorylation-resistant) YAP in ∼1% of hepatocytes led to the formation of highly proliferative and poorly differentiated tumors in ∼4 mo.…”