The cellular and molecular origin of tumor-associated macrophages

TLDR

Macrophages, an evolutionarily ancient cell type essential for tissue homeostasis and immune defense, are now recognized as regulators of diseases such as cancer. In mice, mammary tumors recruit tumor‑associated macrophages that differ from normal tissue macrophages, express Vcam1, proliferate from inflammatory monocytes, depend on RBPJ for differentiation, and whose depletion restores cytotoxic T‑cell activity and suppresses tumor growth, highlighting a distinct tumor‑elicited inflammatory pathway with therapeutic potential.

Abstract

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases, including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an “alternatively activated” phenotype. TAM terminal differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy.