Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes

Abstract

Tumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets of TAMs and provide markers for their identification. Furthermore, in search of the TAM progenitors, we show that the tumor-monocyte pool almost exclusively consisted of Ly6C hi CX 3 CR1 low monocytes, which continuously seeded tumors and renewed all nonproliferating TAM subsets. Interestingly, gene and protein profiling indicated that distinct TAM populations differed at the molecular level and could be classified based on the classic (M1) versus alternative (M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor antigen presenters, but could suppress T-cell activation, albeit by using different suppressive mechanisms. Together, our data help to unravel the complexities of the tumor-infiltrating myeloid cell compartment and provide a rationale for targeting specialized TAM subsets, thereby optimally "re-educating" the TAM compartment. Cancer Res; 70(14); 5728-39. ©2010 AACR.

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…IDO is also produced by MDSCs, regulatory dendritic cells and TAMs [6,52,125,126]. Silencing of IDO within the tumor using Salmonella typhimurium as a tumor-homing vector to deliver a short-hairpin RNA targeting IDO, allowed tumor infiltration of activated ROS-producing neutrophils and consequent tumor cell death [127].…”

Monocytes and Macrophages in Cancer: Development and Functions

“…1). In cancer, it is becoming clear that TAMs, like other members of the myeloid family, are incredible heterogeneous and depending on the tissue and type of tumor, the stage of tumor progression and location within the tumor tissue, different subpopulations of TAMs may differ considerably in terms of function and phenotype [27,56].…”

“…A recent study, using multiple mouse tumor models, demonstrated that multiple subpopulations of TAMs (and/or potentially monocyte-derived transition stages) could be consistently identified based on their expression of surface markers such as Ly6C and MHC [56]. These sub-populations localized to different regions of the tumor microenvironment (such as hypoxic and normoxic regions) and had distinct functions.…”

“…These sub-populations localized to different regions of the tumor microenvironment (such as hypoxic and normoxic regions) and had distinct functions. In addition, the relative frequencies of these subsets changed as the tumor microenvironment changed during disease progression [27,56].…”

“…Unfortunately, the tremendous heterogeneity of macrophage populations and redundancy of cell-surface markers has made it difficult to use adaptive immune-based techniques, such as cytotoxic T cells (CTLs) or monoclonal antibodies, to specifically target TAMs. However, recent comprehensive gene and protein expression analyses have identified potential TAM-specific profiles that could be used for antigen-specific therapies [56,92]. For example, DNA vaccines against MHC class I-restricted epitopes derived from legumain were developed to generate TAM-specific CTLs.…”