Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer

Abstract

Tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs), have been implicated in tumor progression. We recently described a lineage of mouse monocytes characterized by expression of the Tie2 angiopoietin receptor and required for the vascularization and growth of several tumor models. Here, we report that TIE2 expression in human blood identifies a subset of monocytes distinct from classical inflammatory monocytes and comprised within the less abundant "resident" population. These TIE2-expressing monocytes (TEMs) accounted for 2% to 7% of blood mononuclear cells in healthy donors and were distinct from rare circulating endothelial cells and progenitors. In human cancer patients, TEMs were observed in the blood and, intriguingly, within the tumors, where they represented the main monocyte population distinct from TAMs. Conversely, TEMs were hardly detected in nonneoplastic tissues. In vitro, TEMs migrated toward angiopoietin-2, a TIE2 ligand released by activated endothelial cells and angiogenic vessels, suggesting a homing mechanism for TEMs to tumors. IntroductionHematopoietic cells of diverse lineages contribute to tumor progression. [1][2][3][4][5][6][7] Among these cells, tumor-associated macrophages (TAMs) play important roles in tumorigenesis. 3,[8][9][10] TAMs derive from circulating monocytes, which differentiate into macrophages upon homing to tumors. In tumors, TAMs play dichotomous functions. Although TAMs may exert direct antitumor activities, 11,12 increasing data indicate that they are skewed by the tumor microenvironment to a protumoral phenotype. 8,13 Indeed, TAMs can blunt antitumor immunity and stimulate angiogenesis, cell migration, invasion, and metastasis. 3,9 Whereas the divergent TAM functions (ie, antitumoral and protumoral activities) are thought to be contextually modulated by the tumor microenvironment, 8 emerging data suggest that distinct subsets of circulating monocytes exist that are committed to specific functions, including tissue remodeling and proangiogenic activity. [14][15][16] In this regard, we recently identified in mouse tumor models a subset of tumor-infiltrating monocytes characterized by the expression of the angiopoietin receptor Tie2/Tek, 15,17 a molecule previously known to be restricted to endothelial and hematopoietic stem cells. 18,19 In mice, Tie2-expressing monocytes (TEMs) home to tumors, where they are required for angiogenesis. Indeed, selective elimination of TEMs by a suicide gene strategy prevented angiogenesis and induced tumor regression. 15,17 In these tumor models, angiogenesis was inhibited despite the fact that TAM recruitment to tumors was not impaired, indicating that a specific subset of myeloid-lineage cells was primarily responsible for promoting angiogenesis. This concept has received support from other studies that reported proangiogenic activity of selected myeloid cell subsets in mouse tumors, including VEGFR-1 ϩ CD11b ϩ myeloid cells, Gr-1 ϩ CD11b ϩ myeloid suppressor cells, and CD11c ϩ MHC-II ϩ dendritic cell prec...

The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-B-cell lymphoma

“…Next, a considerable body of evidence highlights the role of myeloid-lineage cells in supporting tumor angiogenesis, including a subpopulation of monocytes expressing the angiopoietin-2 receptor Tie2. 49,50 Given the role of macrophages in lymphomagenesis, peripheral blood monocytes may represent an important reservoir of macrophage precursors. To address this possibility, the density of CD68 þ lymphomaassociated macrophages in lymph nodes was examined in this study (data not shown).…”

Monocytes and Macrophages in Cancer: Development and Functions

“…Of note, it might be a very standard physiological reaction of macrophages to respond to tissue hypoxia and initiate, or support, angiogenesis and not at all specific to the tumor environment. Although most TAM populations have been shown to play a role in vascular growth, the Tie2-expressing monocyte/macrophages (TEMs) seem to be a critical promoter of tumor angiogenesis [28,[75][76][77]. TEMs are a small subset of tumor-associated myeloid cells characterized by the expression of the Ang-2 receptor Tie2 [41,77,78].…”

“…Although most TAM populations have been shown to play a role in vascular growth, the Tie2-expressing monocyte/macrophages (TEMs) seem to be a critical promoter of tumor angiogenesis [28,[75][76][77]. TEMs are a small subset of tumor-associated myeloid cells characterized by the expression of the Ang-2 receptor Tie2 [41,77,78]. They derive from circulating Tie2-expressing monocytes, which are recruited into the hypoxic areas of solid tumors by hypoxia-induced, endothelial-derived chemotactic factors, such as Ang-2 and CXCL12 (the CXCR4 ligand) [76][77][78].…”

“…TEMs are a small subset of tumor-associated myeloid cells characterized by the expression of the Ang-2 receptor Tie2 [41,77,78]. They derive from circulating Tie2-expressing monocytes, which are recruited into the hypoxic areas of solid tumors by hypoxia-induced, endothelial-derived chemotactic factors, such as Ang-2 and CXCL12 (the CXCR4 ligand) [76][77][78].…”

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

“…slanDCs are known to partially overlap 12 with the heterogeneous population of the CD16 þ monocytes among PBMC (plots illustrating the gating strategy to identify the non-classical (CD14 dim /CD16 þ ), intermediate (CD14 þ /CD16 þ ) and classical (CD14 þ /CD16 À ) monocyte subsets, as well as slanDCs within the CD14 dim / CD16 þ monocytes are displayed in Fig. 7a) that have been also shown to include the Tie2-expressing monocytes (known as TEMs) 26 . The latter cells generate a perivascular cell population endowed with a prominent pro-angiogenic potential in a variety of human and mouse primary tumours, including human carcinomas 26,27 .…”