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The AAPS Journal

, 21:18 | Cite as

Tumor-Targeted Chemoimmunotherapy with Immune-Checkpoint Blockade for Enhanced Anti-Melanoma Efficacy

  • Man Li
  • Yuting Yang
  • Chaoqun Xu
  • Jiaojie Wei
  • Yingke Liu
  • Xingli Cun
  • Qianwen Yu
  • Xian Tang
  • Sheng Yin
  • Zhirong Zhang
  • Qin He
Research Article
  • 73 Downloads

ABSTRACT

Chemoimmunotherapy with chemotherapeutics and immunoadjuvant inhibits tumor growth by activating cytotoxic T cells. However, this process also upregulates the expression of PD-1/PD-L1 and consequently leads to immune suppression. To maximize the anti-tumor immune responses and alleviate immunosuppression, PD-L1 antibody was combined with paclitaxel (PTX) and the immunoadjuvant α-galactosylceramide (αGC), which were coencapsulated into pH-sensitive TH peptide-modified liposomes (PTX/αGC/TH-Lip) to treat melanoma and lung metastasis. Compared to treatment with PD-L1 antibody or PTX/αGC/TH-Lip alone, the combination of PD-L1 antibody and PTX/αGC/TH-Lip further elevated the tumor-specific cytotoxic T cell responses and promoted apoptosis in tumor cells, leading to enhanced anti-tumor and anti-metastatic effects. In adoptive therapy, PD-L1 antibody further alleviated immunosuppression and enhanced the anti-tumor effect of CD8+ T cells. The combination of PD-L1 antibody and chemoimmunotherapy PTX/αGC/TH-Lip provides a promising strategy for enhancing treatment for melanoma and lung metastasis.

KEY WORDS

α-galactosylceramide chemo-immunotherapy combined strategy immunosuppression PD-L1 antibody 

Notes

Funding

We acknowledge the financial support of the National Natural Science Foundation of China (Nos. 81690261 and 81703450) and the Fundamental Research Funds for Central Universities (2018SCU12026, the Postdoctoral Foundation of Sichuan University).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest

Supplementary material

12248_2018_289_MOESM1_ESM.docx (2.8 mb)
ESM 1 The release profile of PTX/αGC-TH-Lip, PTX-TH-Lip and free PTX at pH 6.0 and 7.4. The serum stability of PTX/αGC-TH-Lip and PTX/αGC-PEG-Lip. Pilot study to determine the optimal interval of PD-L1 antibody and PTX/αGC-TH-Lip. Tumor volume of individual mouse treated with PTX/αGC-Lip+anti-PD-L1, PTX/αGC-Lip, anti-PD-L1 or HEPES buffer. Semiquantitative analysis of TUNEL staining. The H&E staining of major organs of tumor-bearing mice. (DOCX 2906 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Man Li
    • 1
  • Yuting Yang
    • 1
  • Chaoqun Xu
    • 2
  • Jiaojie Wei
    • 1
  • Yingke Liu
    • 3
  • Xingli Cun
    • 1
  • Qianwen Yu
    • 1
  • Xian Tang
    • 1
  • Sheng Yin
    • 1
  • Zhirong Zhang
    • 1
  • Qin He
    • 1
  1. 1.Key Laboratory of Drug Targeting, Ministry of Education, West China School of PharmacySichuan UniversityChengduPeople’s Republic of China
  2. 2.Sichuan Academy of Chinese Medicine ScienceChengduPeople’s Republic of China
  3. 3.West China School of StomotologySichuan UniversityChengduPeople’s Republic of China

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