2. Academic Validation
  3. Hydroxyapatite nanoparticles promote TLR4 agonist-mediated anti-tumor immunity through synergically enhanced macrophage polarization

Hydroxyapatite nanoparticles promote TLR4 agonist-mediated anti-tumor immunity through synergically enhanced macrophage polarization

  • Acta Biomater. 2023 Apr 20;S1742-7061(23)00219-2. doi: 10.1016/j.actbio.2023.04.027.
Ruiqi Wang 1,  Yuchen Hua 2,  Hongfeng Wu 2,  Jingyu Wang 3,  You-Cai Xiao 4,  Xuening Chen 2,  Qiang Ao 5,  Qin Zeng 6,  Xiangdong Zhu 7,  Xingdong Zhang 8
Affiliations

Affiliations

  • 1 National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China, 610064; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan University, Chengdu, China, 610041.
  • 2 National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China, 610064; College of Biomedical Engineering, Sichuan University, Chengdu, China, 610064.
  • 3 College of Biomedical Engineering, Sichuan University, Chengdu, China, 610064.
  • 4 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan University, Chengdu, China, 610041.
  • 5 NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China, 610064; College of Biomedical Engineering, Sichuan University, Chengdu, China, 610064.
  • 6 National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China, 610064; NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China, 610064; College of Biomedical Engineering, Sichuan University, Chengdu, China, 610064. Electronic address: qzeng8156@scu.edu.cn.
  • 7 National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China, 610064; College of Biomedical Engineering, Sichuan University, Chengdu, China, 610064. Electronic address: zhu_xd1973@scu.edu.cn.
  • 8 National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China, 610064; NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China, 610064; College of Biomedical Engineering, Sichuan University, Chengdu, China, 610064.
PMID: 37086827 DOI: 10.1016/j.actbio.2023.04.027
Abstract

Macrophages represent the most prevalent immune cells in the tumor micro-environment, making them an appealing target for tumor immunotherapy. One of our previous studies showed that hydroxyapatite nanoparticles (HANPs) enhanced Toll-like Receptor 4 (TLR4) signal transduction in macrophages. This study was proposed to investigate how HANPs manipulated the phenotype and function of macrophage against 4T1 tumors in the presence or absence of MPLA, a low toxic Toll-like Receptor 4 (TLR4) agonist. The results demonstrated that the addition of HANPs to MPLA significantly promoted cytokine secretion and macrophage polarization toward a tumoricidal M1 phenotype. Further, the resulting supernatant from HANPs/MPLA co-stimulated macrophages enhanced 4T1 tumor cells Apoptosis compared to that from macrophages treated with a single component or PBS control. In particular, we found HANPs elicited immunogenic cell death (ICD) indicated by the increased expression of "danger signals", including HMGB1, CRT and ATP in 4T1 cells. Subsequently, the ICD derivatives-containing supernatant from HANPs-treated 4T1 cells activated macrophage and shifted the phenotype of the cells toward M1 type. Moreover, in a tumor-bearing mice model, HANPs and MPLA synergistically delayed tumor growth compared to PBS control, which was positively associated with the promoted macrophage polarization and ICD induction. Therefore, our findings demonstrated a potential platform to modulate the function of macrophages, and shed a new insight into the mechanism involving the immunomodulatory effect of HANPs for tumor therapy. STATEMENT OF SIGNIFICANCE: Polarizing macrophage toward tumoricidal phenotype by harnessing Toll-like Receptor (TLR) agonists has been proven effective for tumor immunotherapy. However, the immunomodulatory potency of TLR agonists is limited due to immune suppression or tolerance associated with TLR activation in immune cells. Herein, we introduced hydroxyapatite nanoparticles (HANPs) to MPLA, a TLR4 Agonist. The results demonstrated that the addition of HANPs to MPLA promoted macrophage shift toward tumoricidal M1 phenotype, supported a "hot" tumor transformation, and delayed 4T1 tumor growth. Moreover, we found that HANPs elicited immunogenic cell death that produced "danger" signals from Cancer cells thereby further facilitated macrophage polarization. This work is significant to direct the rational design of HANPs coupled with or without TLR agonists for tumor immunotherapy.

Keywords

Hydroxyapatite nanoparticles; Immunogenic cell death; Macrophage; Polarization; Toll-like receptor 4; Tumor immunotherapy.

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