Monocytes TIE(2)d up in murky business

TIE2-expressing monocytes, a specialized population of tumor-infiltrating monocytes committed to promoting angiogenesis, are now found also in human tumors.

Tumor-infiltrating myeloid cells have been implicated in tumor progression. Monocyte populations with different immunophenotypes have been isolated to date from murine or human tumors by various groups and have been shown to carry out diverse functions, all of which promote tumor growth. The full characterization of these populations is thus expected to provide new opportunities for cancer therapy. In this issue of Blood, Venneri and colleagues describe monocytes expressing the angiopoietin receptor TIE2 in human solid tumors. This is an important finding, as their murine counterparts, previously described by the same group, are indeed required for the vascularization and growth of several murine tumor types.¹  Importantly, human TIE2-expressing monocytes (TEMs) represented the main monocyte population isolated from human solid tumors other than canonical tumor-associated macrophages (TAMs). In this report, TEMs markedly promoted angiogenesis in xenotransplanted human tumors, while canonical TAMs depleted of TEMs did not. This complements previous evidence that monocyte populations are paramount for tumor angiogenesis, or sprouting of endothelial cells from existing vessels, and perhaps vasculogenesis, which entails differentiation of recruited endothelial myeloid progenitors into endothelial cells.

In the mouse, Gr-1⁺ CD11b⁺ tumor monocytes (or myeloid suppressor cells) promote angiogenesis via paracrine mechanisms and function as vascular-cell precursors.²  Similarly, VEGFR-1⁺ CD11b⁺ monocytes are recruited by vascular endothelial growth factor and exert proangiogenic activity in mouse tumors. Additional monocyte precursors committed to tumor angiogenesis and possibly vasculogenesis include the vascular leukocytes, a subset of CD11c⁺ MHC-II⁺ dendritic-cell precursors expressing endothelial vascular markers VE-cadherin, CD34, and CD146. In the mouse, these have been recruited to tumors via CCR6, whereupon they greatly accelerated tumor vascularization and growth.³  Human vascular leukocytes have been described in high numbers in human ovarian cancer and have been shown to form human neovessels in the mouse, demonstrating vascular commitment.⁴  Venneri and colleagues have shown that human TIE2-expressing monocytes also demonstrate clear commitment to tumor angiogenesis, as they can migrate towards angiopoietin-2, a TIE2 ligand released by activated endothelial cells and angiogenic vessels, and that they largely contribute to the tumor angiogenic process in vivo.

The discovery of these tumor-bound monocyte populations offers numerous therapeutic opportunities. First, given the propensity of TEMs as well as vascular leukocytes (VLCs) and possibly other TAMs to home to tumors, and specifically to the tumor vasculature, they can be used as cellular vectors to deliver therapeutic payloads to these targets in a “Trojan horse” cell-based therapy approach. Second, their selective elimination is expected to provide therapeutic benefit. Previous evidence in the mouse has shown that depletion of TEMs through genetic manipulation⁵  or of VLCs through immunotoxic methods⁴  prevented angiogenesis and induced tumor regression. Identifying specific molecular targets in these populations will therefore be important in achieving selective elimination without toxicity, but could yield important results in the clinic. Finally, understanding the mechanisms that induce the differentiation of myeloid precursors towards these lineages may provide novel ways to re-educate these cells towards a tumoricidal, rather than a cancerophilic, phenotype. Time will show whether one or more of these tumor-infiltrating monocyte populations represent indeed one of tumors' Achilles heels in the human.