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
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Qian Chen, Ying Bai, Qian Dai, Le Zhang, Jing Qiu, Wang Xingmin, Lu Jiang, Xiaomei Hu, Kebin Zhang, Junzhi Xiong, Xiaomei He, Li Yuanyuan, Hong Zhang, Jin Peng, Rong Xin, Qiaoqiao Li, Hua Yu, Halei Sheng, and Defeng Li
- Subjects
Cancer Research ,biology ,medicine.medical_treatment ,tumoricidal efficacy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Nitric oxide ,Nitric oxide synthase ,chemistry.chemical_compound ,PcrV–TLR4 interaction ,Cancer immunotherapy ,chemistry ,Oncology ,Apoptosis ,TAM reeducation ,Cancer cell ,Cancer research ,medicine ,TLR4 ,biology.protein ,Protein kinase B ,RC254-282 ,PI3K/AKT/mTOR pathway ,Original Research ,Pseudomonas aeruginosa PcrV protein ,TLR4/PI3K/AKT/mTOR-glycolysis-NO feedback loop - 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