Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma

Abstract

Background & Aims: Macrophages (Mu) represent a major component of tumor tissues and play an important role in both tumor progression and therapeutic response. Although tumor Mu are generally considered to be derived from circulating monocytes, emerging evidence indicates that tissue Mu pools can be maintained by self-renewal. We aimed to elucidate the contribution, phenotype, and regulatory mechanisms of proliferating Mu in human hepatocellular carcinoma (HCC). Methods: Flow cytometry analyses were performed to examine the presence and phenotype of proliferating Mu in fresh HCC tissues. Dual immunofluorescence staining was applied to analyze the prognostic value of proliferating Mu. The underlying regulatory mechanisms were examined using human monocytederived Mu. Results: Tumor-infiltrating Mu exhibited a significantly higher proliferative capacity than Mu in non-tumor tissues. A higher level of Mu proliferation was positively correlated with Mu density in the tumor and a poor prognosis in patients with HCC. Proliferating Mu were less differentiated (with increased CD206 expression) and were induced by the tumor cell-derived soluble small molecule, adenosine, but not proteins, lipids, or large peptides. Mechanistic studies demonstrated that autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) released by tumor-stimulated Mu could enhance A2A receptor expression on Mu and function synergistically with adenosine to elicit Mu proliferation in HCC. Conclusions: Local Mu proliferation is an important mechanism for Mu accumulation in HCC tissues. Tumor-derived adenosine functions synergistically with autocrine GM-CSF released from activated Mu, which promotes Mu proliferation. Thus, selective modulation of Mu accumulation at the source may provide a novel strategy for cancer therapy. Lay summary: Tumor-associated macrophages (TAMs) have been reported to play an essential role in both tumor progression and therapeutic response. A fundamental understanding of the mechanisms that regulate macrophage accumulation in tumors will undoubtedly lead to the development of strategies to target macrophages with high specificity and efficiency. The current study unveils a novel mechanism by which local proliferation is linked to macrophage accumulation in the tumor milieu, identifying potential targets for future immune-based anticancer therapies.

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…In addition, adenosine inhibits TNF-α and IL-12 release and augments IL-10 and vascular endothelial growth factor (VEGF) [ 122 ] production by LPS or bacteria-activated macrophages [ 123 , 124 , 125 , 126 ] and promotes alternative macrophage activation [ 127 ]. More recently, it has been reported that adenosine is also involved in TAMs proliferation [ 128 ]. Mechanistic studies have demonstrated that adenosine released from hepatoma cells could promote macrophages proliferation through the A2A receptor, and tumor-derived adenosine functions synergistically with autocrine GM-CSF released in TME, supporting macrophages proliferation ( Figure 2 ).…”

“…The activation of the IL-1β/IL-1R signaling pathway in tumors by TAMs is correlated with the acquisition of a CSC-like phenotype [ 96 ]. As observed in other tumor types, adenosine (ADO) pathways may be involved in MM cells-TAMs interaction, inducing the release of pro-tumoral cytokines and promoting TAMs proliferation [ 115 , 127 , 128 ]. Although limited data indicate its involvement in MPM immunosuppression [ 117 ], a deep investigation is required.…”

ASF1B Serves as a Potential Therapeutic Target by Influencing Cell Cycle and Proliferation in Hepatocellular Carcinoma

“…COX regression analysis showed that ASF1B was an independent risk factor for HCC prognosis, and ROC curve analysis showed that ASF1B expression had certain predictive value for survival evaluation of HCC patients at 1, 3 and 5 years.ASF1B expression in HCC patients increased with tumor stage and grade progression, suggesting that ASF1B is associated with HCC disease progression. Recently, an increasing number of studies have found a correlation between cancer progression and tumor immune infiltration ( 30 , 31 ). Through public data mining, we also found a certain correlation between the expression of ASF1B and the immune infiltration of HCC, which is consistent with the conclusions of current reports ( 28 , 29 ).…”

Macrophage Identification In Situ

“…It is usually thought that TAM macrophages originate from blood monocytes [111], but in certain brain and lung (murine model animal) cancers, the tumors originated from tissue-resident macrophages [28]. M1-like TAM macrophages express CD68, CD80, CD86 and CD169 [110,112] and the M2-like class of TAM macrophages show strong CD204, CD206 and CD163 expression [112][113][114]. In addition, a new marker for these cells was recently found, the disulfide-isomerase A3 (PDIA3) receptor [115].…”