1. Pseudomonas aeruginosa PcrV Enhances the Nitric Oxide-Mediated Tumoricidal Activity of Tumor-Associated Macrophages via a TLR4/PI3K/AKT/mTOR-Glycolysis-Nitric Oxide Circuit
- Author
-
Hua Yu, Ying Bai, Jing Qiu, Xiaomei He, Junzhi Xiong, Qian Dai, Xingmin Wang, Yuanyuan Li, Halei Sheng, Rong Xin, Lu Jiang, Qiaoqiao Li, Defeng Li, Hong Zhang, Le Zhang, Qian Chen, Jin Peng, Xiaomei Hu, and Kebin Zhang
- Subjects
Pseudomonas aeruginosa PcrV protein ,TAM reeducation ,tumoricidal efficacy ,TLR4/PI3K/AKT/mTOR-glycolysis-NO feedback loop ,PcrV–TLR4 interaction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
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.
- Published
- 2021
- Full Text
- View/download PDF