Tumor associated macrophages
Macrophage originates from progenitors in the bone marrow and enters the peripheral blood. During homeostasis and inflammation, they migrate into tissues and differentiate into macrophage following exposure to local growth factors, proinflammatory cytokines, and microbial products. The function of macrophages in the tumor is multiple[62]. As for tumor associated macrophages (TAM), studies have found that the number of CD68 positive and CD204 positive TAM in EGFR mutant NSCLC tumor tissues is less than that of EGFR wild type, and the prognosis is better[63]. Moreover, EGFR mutated lung cancer with high infiltrating CD204 positive TAM had high aggressiveness and poor prognosis[64]. Another study found that EGFR-TKIs resistant lung cancer was correlated to tumor infiltrating CD68 positive TAM and S100A9 positive MDSC, which resulted in resistance through the NF-κB pathway[65]. Two major macrophage subpopulations with different functions include classically activated or inflammatory (M1) and alternatively activated or anti-inflammatory (M2) macrophages have been recognized. M1 macrophage has robust anti-tumoral activity whereas M2 macrophage promotes tumor formation and progression[66].CD68 positive and CD204 positive TAM is M2 type macrophage. It was found that the level of M2 type macrophage in EGFR-TKIs resistant lung cancer was higher than that in EGFR-TKI sensitive lung cancer[67]. Therefore, it can be inferred that EGFR-TKIs resistance is related to M2 type TAM, and reducing M2 type TAM may reverse EGFR-TKIs resistance.