Identification and manipulation of tumor associated macrophages in human cancers

Abstract

Evading immune destruction and tumor promoting inflammation are important hallmarks in the development of cancer. Macrophages are present in most human tumors and are often associated with bad prognosis. Tumor associated macrophages come in many functional flavors ranging from what is known as classically activated macrophages (M1) associated with acute inflammation and T-cell immunity to immune suppressive macrophages (M2) associated with the promotion of tumor growth. The role of these functionally different myeloid cells is extensively studied in mice tumor models but dissimilarities in markers and receptors make the direct translation to human cancer difficult. This review focuses on recent reports discriminating the type of infiltrating macrophages in human tumors and the environmental cues present that steer their differentiation. Finally, immunotherapeutic approaches to interfere in this process are discussed.

Figure 1

Macrophages and T cells in the tumor micro milieu. Tumors actively attract myeloid cells by the secretion of chemokines which is amongst others driven by hypoxia (I). Once myeloid cells have arrived in the tumor micro milieu several tumor cell produced factors drive the differentiation into a range of different types of macrophages, including M2 macrophages as a consequence of high STAT3 phosphorylation (II). M2 macrophages produce tumor promoting factors, express inhibitory molecules and upon activation produce anti-inflammatory cytokines and metalloproteinase that hamper T-cell function and promote tumor growth (III). Activation of M2 macrophages in the presence of IFNγ - for instance following cognate interaction CD4+ type 1 helper T cells - switch M2 macrophages to pro-inflammatory activated M1 macrophages (IV). M1 macrophages alter the immune suppressed micro milieu by producing IL-12 helping anti-tumor T cells as well as directly attack tumor cells (V).