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

TLDR

Tumor‑associated macrophages are a major stromal component, yet their heterogeneity and monocytic precursors remain poorly defined. We identified functionally distinct TAM subsets in mouse mammary tumors, characterized by Ly6ChiCX3CR1low monocyte precursors, M1/M2‑like molecular signatures, hypoxia‑enriched pro‑angiogenic M2‑like cells that expand with tumor growth, and differential T‑cell suppression, underscoring the need to target specific TAM populations to re‑educate the tumor microenvironment. Cancer Res 70(14):5728–39; ©2010 AACR.

Abstract

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 Ly6ChiCX3CR1low 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.