Image_8_Pseudomonas aeruginosa PcrV Enhances the Nitric Oxide-Mediated Tumoricidal Activity of Tumor-Associated Macrophages via a TLR4/PI3K/AKT/mTOR-Glycolysis-Nitric Oxide Circuit.tif
Tumor-associated macrophages (TAMs), which display a tumor-supportive M2 phenotype, are closely related to tumor growth and metastasis. The reprogramming of TAMs toward a tumoricidal M1 profile has emerged as an attractive strategy for cancer immunotherapy. In this study, we found that the intratumoral injection of PcrV protein, a component of the Pseudomonas aeruginosa type 3 secretion system, suppressed tumor growth and increased apoptosis, inducible nitric oxide synthase (iNOS) expression, and the percentage of M1-polarized TAMs in tumor tissues. Furthermore, the intratumoral injection of PcrV-primed macrophages exerted a similar tumoricidal effect. In vitro analyses revealed that PcrV reeducated TAMs toward an antitumoral M1 phenotype and augmented their nitric oxide (NO)-mediated cytotoxicity against cancer cells. Mechanistically, we found that these effects were dependent on the activation of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated regulation of a PI3K/AKT/mTOR-glycolysis-NO feedback loop via direct interaction with TLR4. Collectively, these results revealed a potential role for PcrV in cancer immunotherapy through the targeting of TAM plasticity.
History
References
- https://doi.org//10.1016/j.ctrv.2020.102015
- https://doi.org//10.1016/j.it.2019.02.003
- https://doi.org//10.1158/0008-5472.CAN-17-3480
- https://doi.org//10.1186/s13046-018-0878-0
- https://doi.org//10.1016/j.bbacli.2015.06.002
- https://doi.org//10.1158/1078-0432.CCR-14-1781
- https://doi.org//10.1021/acs.molpharmaceut.8b00691
- https://doi.org//10.1038/cmi.2014.28
- https://doi.org//10.1016/j.imbio.2015.06.009
- https://doi.org//10.1111/j.1365-2958.2008.06237.x
- https://doi.org//10.3389/fimmu.2019.00781
- https://doi.org//10.1111/1348-0421.12467
- https://doi.org//10.3389/fmicb.2020.01971
- https://doi.org//10.1016/j.biomaterials.2017.04.043
- https://doi.org//10.1038/s41577-018-0061-z
- https://doi.org//10.1111/cas.14110
- https://doi.org//10.1016/j.yexcr.2018.01.033
- https://doi.org//10.1038/s41374-020-0404-9
- https://doi.org//10.1016/j.bbabio.2008.04.011
- https://doi.org//10.1371/journal.pone.0044081
- https://doi.org//10.1016/j.febslet.2014.07.006
- https://doi.org//10.3389/fimmu.2020.00807
- https://doi.org//10.1186/s13046-019-1138-7
- https://doi.org//10.1155/2016/6058147
- https://doi.org//10.1038/s41577-019-0127-6
- https://doi.org//10.1016/S1471-4906%2802%2902302-5
- https://doi.org//10.1016/j.cell.2010.03.014
- https://doi.org//10.1016/j.it.2011.12.001
- https://doi.org//10.4161/bioe.29266
- https://doi.org//10.2174/157489207782497163
- https://doi.org//10.1038/sj.onc.1210906
- https://doi.org//10.1080/2162402X.2015.1088631
- https://doi.org//10.1016/j.ijbiomac.2018.01.070
- https://doi.org//10.1016/j.biopha.2019.109636
- https://doi.org//10.1007/s40291-018-0361-9
- https://doi.org//10.3390/ijms19092729
- https://doi.org//10.1016/j.ejphar.2013.01.014
- https://doi.org//10.1158/1078-0432.CCR-18-3851
- https://doi.org//10.1080/2162402X.2016.1229725
- https://doi.org//10.1111/cas.13945
- https://doi.org//10.1016/S1089-8603%2802%2900147-7
- https://doi.org//10.3892/ijmm.2012.1171
- https://doi.org//10.1016/j.bcp.2019.113750
- https://doi.org//10.3389/fimmu.2018.01186
- https://doi.org//10.3892/ijo_00000079
- https://doi.org//10.1097/00000441-199311000-00015
- https://doi.org//10.3389/fnmol.2011.00051
- https://doi.org//10.3389/fimmu.2019.01462