MDSC-targeted liposomal all-trans retinoic acid suppresses mMdscs and improves immunotherapy in HBV infection

ABSTRACT

Background

Myeloid-derived suppressor cells (MDSCs) are evolving as a prominent determinant in cancer occurrence and development and are functionally found to suppress T cells in cancer. Not much research is done regarding its involvement in viral infections. This research was designed to investigate the role of MDSCs in hepatitis B virus (HBV) infection and how targeting these cells with our novel all-trans retinoic acid encapsulated liposomal formulation could improve immunotherapy in C57BL/6 mice.

Methods

Ten micrograms (10 μg) of plasmid adeno-associated virus (pAAV/HBV 1.2, genotype A) was injected hydrodynamically via the tail vein of C57BL/6 mice. An all-trans retinoic acid encapsulated liposomal formulation (L-ATRA) with sustained release properties was used in combination with tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor (nRTI) to treat the HBV infection. The L-ATRA formulation was given at a dose of 5 mg/kg intravenously (IV) twice a week. The TDF was given orally at 30 mg/kg daily.

Results

Our results revealed that L-ATRA suppresses MDSCs in HBV infected mice and enhanced T-cell proliferation in vitro. In vivo studies showed higher and improved immunotherapeutic effect in mice that received L-ATRA and TDF concurrently in comparison with the groups that received monotherapy. Lower HBV DNA copies, lower concentrations of HBsAg and HBeAg, lower levels of ALT and AST and less liver damage were seen in the mice that received the combination therapy of L-ATRA + TDF.

Conclusions

In effect, targeting MDSCs with the combination of L-ATRA and TDF effectively reduced mMDSC and improved immunotherapy in the HBV infected mice. Targeting MDSCs could provide a breakthrough in the fight against hepatitis B virus infection.

KEYWORDS:

• Hepatitis B virus infection
• myeloid-derived suppressor cells
• tenofovir disoproxil fumarate
• liposomal all-trans retinoic acid
• immunotherapy
• drug delivery

Author contributions

S Kesse, J Peng, Z Du, R Alolga and Y Xu came up with the design and concept of this work. S Kesse, S Shi, M He, S Ullah and S Jin performed the experiments. S Kesse, R Alolga, J Peng and Y Xu wrote the manuscript. S Shi, R Alolga, S Jin, A Zheng, M He, Y Dai, S Ullah and F Xu assisted in data analysis and interpretation. All authors contributed to the final draft of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We are thankful to Professor Pei-Jer Chen (National Taiwan University College of Medicine) for benevolently providing us with the pAAV/HBV 1.2, genotype A.

Data availability statement

The raw data supporting the findings of this research will be made accessible by the corresponding authors upon reasonable request, without unwarranted reservation.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425247.2024.2317936

Additional information

Funding

This paper was funded by grant support from the National Natural Science Foundation of China (NSFC) No. 81690262 as well as Yunnan Department of Science and Technology No. 202105AE160010.