Integrin ?3 Induces The Expression Of PPAR? To Promote TAMs M2 Polarization In Breast Cancer

The cell adhesion molecule integrin ?3 is widely expressed in various tumor tissues and has functions of promoting tumor invasion,migration and angiogenesis.Clinical data show that in breast cancer,it is closely related to the patient's poor prognosis,significantly affecting the patient's disease-free survival(DFS)and 5-year survival rate.Therefore,a large number of studies have attempted to target Integrin ?3 to treat tumors and make progress.Integrin ?3 antagonist(Cilengitide)has shown good efficiency in clinical phase I trials of breast cancer,which inhibits tumor cell grow th by inhibiting angiogenesis and inhibiting tumor blood supply;it can also be associated with paclitaxel Combined use,mediating the mechanism of different tumor killings and,exerting a stronger therapeutic effect.The above reports show that Integrin P3 has a good application value in the clinical treatment of tumors.Therefore,a further understanding of the role of Integrin P3 in tumor progression and immune microenvironment remodeling and its regulatory mechanisms will help to promote its clinical application,expand its scope of application,and provide a theoretical basis for clinical drug use.Tumor-associated macrophages(TAMs)are the most abundant immune cells in the immune microenvironment of breast cancer tumors.They usually display the M2-like phenotype,which has the function of promoting tumor metastasis and mediating immunosuppression.Doffer receptors CD 163,CD204 and CD206;a large number of secretory immunosuppressive cytokines,such as IL-10,TGF-?,etc.;high expression of arginase,regulation of arginine metabolism to produce polyamines,promote breast cancer cell growth and proliferation.Therefore,in breast cancer,massive infiltration of TAMs is often closely related to adverse clinical outcomes.It is reported that Integrin?3 is involved in the regulation of TAMs,and the macrophage M1 polarization is affected by the JAK-STAT1 pathway,which inhibits the anti-tumor immune response of macrophages.Similarly,studies have reported that Integrin ?3 promotes macrophage M2 polarization;however,some researchers believe that Integrin ?3 can inhibit STAT6 phosphorylation and thus affect macrophage M2 polarization.Therefore,to clarify the effect of Integrin ?3 on the phenotype and function of TAMs,and to elucidate the molecular regulation mechanism,it is of great significance to understand the role of Integrin ?3 in regulating tumor immune microenvironment.Based on this,we combined the molecular and cellular models,combined with the use of small-molecule inhibitors Cyclo(RGDyK)and CRISPR/Cas9 gene editing technology,to explore the effects of Integrin ?3 on the function of breast cancer TAMs.Integrin ?3 regulates the molecular basis of M2 type polarization of macrophages,which provides a solid experimental basis for the subsequent study of targeting Integrin?3 to regulate TAMs function,remodeling tumor immune microenvironment and affecting breast cancer progression.Experiment result shows:1.In a mouse model of breast cancer,TAMs overexpress Integrin ?3.2.In the in vitro induced TAMs model,the addition of Cyclo(RGDyK)treatment did not affect the expression of TAMs-promoting genes,such as VEGF,TGF-P,MMP2,MMP9,but M2 phenotype-related genes:Arg1,CD206,Ym1,Fizzl,etc.were significantly down-regulated;macrophage antigen presentation ability increased.3.In the IL-4 induced M2-type polarization model,macrophage Integrin ?3 was significantly increased,and after Cyclo(RGDyK)treatment,M2 phenotype-related genes:Arg1,CD206,Ym1,Fizzl,etc.were significantly down-regulated;the phagocytosis ability of the cells is decreased;the antigen presentation ability is improved.4.Integrin ?3 was knocked out,which has similar macrophage phenotype and function changes as small molecule treatment.Further studies found that Integrin ?3 can directly regulate PPARy but not STAT6 signaling to mediate M2 type polarization of macrophages.5.Integrin ?3 can also regulate the function of PPARy lipid synthesis,suggesting that it may regulate the macrophage phenotype by affecting lipid metabolism.In summary,our studies confirm the high expression of Integrin ?3 in breast cancer TAMs and IL-4 induced M2-type polarized macrophages through a series of in vivo and in vitro experiments and specifically regulates PPARy instead of STAT6 signaling.Guided macrophage M2 type polarization.This study explored the role and mechanism of Integrin ?3 in regulating the phenotype and function of breast cancer TAMs and enriched the theoretical basis for the clinical treatment of breast cancer targeting Integrin ?3.Targeting Integrin ?3 in TAMs and its downstream effector molecules become a new immune strategy based on immune regulation.