M3 Macrophages Stop Division of Tumor Cells In Vitro and Extend Survival of Mice with Ehrlich Ascites Carcinoma

Abstract

BackgroundM1 macrophages target tumor cells. However, many tumors produce anti-inflammatory cytokines, which reprogram the anti-tumor M1 macrophages into the pro-tumor M2 macrophages. We have hypothesized that the problem of pro-tumor macrophage reprogramming could be solved by using a special M3 switch phenotype. The M3 macrophages, in contrast to the M1 macrophages, should respond to anti-inflammatory cytokines by increasing production of pro-inflammatory cytokines to retain its anti-tumor properties. Objectives of the study were to form an M3 switch phenotype in vitro and to evaluate the effect of M3 macrophages on growth of Ehrlich ascites carcinoma (EAC) in vitro and in vivo.Material/MethodsTumor growth was initiated by an intraperitoneal injection of EAC cells into C57BL/6J mice.Results1) The M3 switch phenotype can be programed by activation of M1-reprogramming pathways with simultaneous inhibition of the M2 phenotype transcription factors, STAT3, STAT6, and/or SMAD3. 2) M3 macrophages exerted an anti-tumor effect both in vitro and in vivo, which was superior to anti-tumor effects of cisplatin or M1 macrophages. 3) The anti-tumor effect of M3 macrophages was due to their anti-proliferative effect.ConclusionsDevelopment of new biotechnologies for restriction of tumor growth using in vitro reprogrammed M3 macrophages is very promising.

Role of Macrophages in the Progression and Regression of Vascular Calcification

“…M2 can be further divided into four subsets, namely M2a, M2b, M2c, and M2d, under different stimuli (Murray et al, 2014). TGF stimulates macrophages to differentiate into M3, which has the ability to suppress tumor growth (Kalish et al, 2017). CXCL4, a platelet-derived chemokine, is a potent stimulus that promotes macrophage polarization into the M4 phenotype, which has reduced phagocytosis and significantly downregulates CD163 expression (Gleissner et al, 2010).…”

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

“…[50][51][52] Macrophages are capable of differentiating into six additional subpopulations: regulatory (Mreg), hematophage-associated (Mha), oxidative (Mox), M3, M4, and M17 macrophages ( Table 1). [53][54][55][56] Mreg macrophages respond to the stimulation of Treg cells and are responsible for inducing the repair response and inhibiting triggering of mechanisms that produce pro-inflammatory cytokines in tissue lesions. [57][58][59] Mox macrophages differ from the other cell types in expressing oxidized 1palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine and producing HO-1 and sulfiredoxin-1.…”

A vicious circle in breast cancer: The interplay between inflammation, reactive oxygen species, and microRNAs

“…This observation, support the hypothesis about the transition of M1 cells to M3 cells during tumor proliferation ( 78 ). Kalish et al reported that the M3 phenotype exhibited an antiproliferative antitumor effect in vitro , and prolonged the survival time of mice with Ehrlich ascites carcinoma ( 79 ). Nevertheless, more studies are needed to fully characterize and understand the activity of the M3 macrophages.…”