FIGURE 3.

Intratumoral differentiation of the monocyte/macrophage lineage. Three conserved monocyte/macrophage differentiation trajectories are identified from human TME. The first trajectory is the tumor infiltration and activation of conventional monocytes (CD14⁺CD16^–) from the vasculature into activated intratumoral monocytes; the second trajectory is the ongoing intratumoral macrophage differentiation from the activated intratumoral monocytes into tumor-associated macrophages (TAMs), characterized by high expression of HLA-DR, CD68 and CD64; the third trajectory is the differentiation of circulating conventional monocytes (CD14⁺CD16^–) into early immigrant macrophages (HLA-DR^intCD192⁺) and then continue to tissue-resident macrophages (HLA-DR^intCD206⁺) through stepwise tissue adaptation within the adjacent normal tissue. Tissue-resident macrophages (HLA-DR^intCD206⁺) can then across the invasive margin to infiltrate tumor and potentially be converted to TAMs (HLA-DR^hiCD68⁺CD64⁺). The intratumoral monocyte may also differentiate into myeloid-derived suppressor cells (MDSCs), whose presence often negatively associates with clinical outcomes.