Transient Kupffer cell depletion and subsequent replacement by infiltrating monocyte‐derived cells does not alter the induction or progression of hepatocellular carcinoma

Abstract

Due to a combination of rapid disease progression and the lack of curative treatment options, hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Infiltrated, monocyte‐derived, tumor‐associated macrophages are known to play a role in HCC pathogenesis, but the involvement of Kupffer cells (KCs) remains elusive. Here, we used the Clec4F‐diphteria toxin receptor transgenic mouse model to specifically investigate the effect of KC depletion on HCC initiation, progression and neoplastic growth following liver resection. For this purpose, several HCC mouse models with varying underlying etiologies were used and partial hepatectomy was performed. Our results show that in HCC, developed on a fibrotic or non‐alcoholic steatohepatitis background, depletion of embryonic KCs at the onset of HCC induction and the subsequent replacement by monocyte‐derived KCs does not affect the tumor burden, tumor microenvironment or the phenotype of isolated KCs at end‐stage disease. In non‐chronic liver disease‐associated diethylnitrosamine‐induced HCC, ablation of Clec4F+ KCs did not alter tumor progression or neoplastic growth following liver resection. Our results show that temporal ablation of resident KCs does not impact HCC pathogenesis, neither in the induction phase nor in advanced disease, and indicate that bone marrow‐derived KCs are able to swiftly repopulate the available KC niche and adopt their phenotype.

Hepatoblastoma exhibits a predominantly myeloid immune landscape and reveals opportunities for macrophage targeted immunotherapy

“…Several studies have demonstrated that human KCs can be identified on RNA level by expression of MARCO, CD5L, VSIG4 and TIMD4 21,[44][45][46][47] . Our scRNA-seq analysis of chemotherapytreated HB shows that TAMs have low MARCO expression and upregulated inflammatory markers, similar to transcriptional profiles of inflammatory monocyte-derived macrophages identified in several liver disease settings 30,[46][47][48][49][50] . Surprisingly, we find that TAMs express KC markers (CD5L, VSIG4, TIMD4) and display high tissue residency scores in HB.…”

Mechanisms of tumor-associated macrophages affecting the progression of hepatocellular carcinoma

“…NOX enzymes were the principal source of ROS. NOX1 and secretion of IL-1α/β and TNF-α facilitated the advancement of hepatic fibrosis and inflammation (Amano et al, 2017;Sun et al, 2017;Vandierendonck et al, 2021). Targeting the phenotype of TAMs and the cytokines they secrete is the key to blocking the progression of the fibrotic liver into HCC (Table 1).…”

“…Danger signals in HCC can activate the inflammatory regulation of KCs and promote drawing immune cells to the liver. The production of CCL2 by tumor cells leads to the absence of embryonic KCs in tissue and promotes the infiltration of monocyte-derived KCs and immature monocytes (M0) ( Thomann et al, 2021 ; Vanderborght et al, 2023 ). Myeloid precursor cells are recruited to infiltrate HCC, and the TME blocks its maturation process.…”

“…Research has indicated that the high infiltration of tumor-associated macrophages (TAMs) in liver cancer is strongly tied to a negative prognosis for patients (Li et al, 2018b). Compared to other organs, the liver has a greater percentage of macrophages (van der Heide et al, 2019). Kupffer cells (KCs), as a stationary tissue-resident macrophage subset of the liver, are positioned in the blood sinuses, which is pivotal in maintaining homeostasis (Lopez et al, 2011;Scott et al, 2016).…”