Frontiers in Oncology (Nov 2021)

Pseudomonas aeruginosa PcrV Enhances the Nitric Oxide-Mediated Tumoricidal Activity of Tumor-Associated Macrophages via a TLR4/PI3K/AKT/mTOR-Glycolysis-Nitric Oxide Circuit

  • 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,
  • Kebin Zhang

DOI
https://doi.org/10.3389/fonc.2021.736882
Journal volume & issue
Vol. 11

Abstract

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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.

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