Drug-Loaded Tumor-Derived Microparticles Elicit CD8+ T Cell-Mediated Anti-Tumor Response in Hepatocellular Carcinoma

Abstract

Background

Hepatocellular Carcinoma (HCC) poses significant challenges due to limited effective treatments and high recurrence rates. Immunotherapy, a promising approach, faces obstacles in HCC patients due to T-cell exhaustion and immunosuppression within the tumor microenvironment.

Methods

Using doxorubicin-loaded tumor-derived microparticles (Dox-TMPs), the mice with H22 ascites model and subcutaneous tumors model were treated. Following the treatment, mice were re-challenged with H22 cells to compare the therapeutic effects and recurrence among different groups of mice, alongside examining the changes in the proportions of immune cells within the tumor microenvironment. Furthermore, Dox-TMPs were combined with anti-PD-1 to further validate their anti-tumor efficacy. In vitro studies using various liver cancer cell lines were conducted to verify the tumor-killing effects of Dox-TMPs. Additionally, CD8+ T cells from the abdominal cavity of tumor-free mice were co-cultured with H22 cells to confirm their specific tumor-killing abilities.

Results

Dox-TMPs demonstrate effective anti-tumor effects both in vitro and in vivo. In vivo, their effectiveness primarily involves enhancing CD8+ T cell infiltration, alleviating T cell immunosuppression, and improving the immune microenvironment to combat tumors. When used in combination with anti-PD-1, their anti-tumor effects are further enhanced. Moreover, some mice treated with Dox-TMPs developed anti-tumor immunity, displaying a self-specific T-cell immune response upon re-challenged with tumor cells. This suggests that Dox-TMPs also have the potential to act as a long-term immune response against tumor recurrence, indicating their capability as a tumor vaccine.

Conclusion

Dox-TMPs exhibit a dual role in liver cancer by regulating T cells within the tumor microenvironment, functioning both as an anti-tumor agent and a potential tumor vaccine.

Graphical Abstract

Keywords:

• liver cancer
• drug-loaded microparticles
• tumor immune microenvironment
• tumor vaccine

Abbreviations

HCC, Hepatocellular Carcinoma; Dox, Doxorubicin; MPs, Microparticles; TMPs, Tumor-derived microparticles; Dox-TMPs, Doxorubicin-loaded tumor-derived microparticles; TME, Tumor immune microenvironment; PD-1/PD-L1, Programmed cell death 1/PD-1 ligand; PS, Penicillin-streptomycin; CFSE, 5(6)-Carboxyfluorescein diacetate N-succinimidyl ester; DAPI, 4’,6-Diamidino-2-Phenylindole; NTA, tracking analysis nanoparticle; HPLC, High Performance Liquid Chromatography.

Acknowledgments

The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license. Graphical Abstract were drawn by Figdraw.

Disclosure

The authors report no conflicts of interest in this work.