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Exosomal miR-125b-5p derived from mesenchymal stromal/stem cell enhances anti-PD-1 therapy in mouse colon cancer
Mengmeng Jiang1,2, Jia Liu3, Shengquan Hu1,2,4
1Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518035, China.
Background:
There is compelling evidence that FoxP3+ regulatory T cells (Tregs) play a critical role in promoting tumor immune evasion. Our prior research demonstrated that the expression of miR-125b-5p directly inhibits Tregs by targeting TNFR2 and FoxP3. Given the significant therapeutic potential of mesenchymal stromal/stem cell (MSC)-derived exosomes (MSC-EXO) in cancer treatment, the potential role of MSC-EXO in augmenting anti-tumor immunotherapy through the delivery of miR-125b-5p remains unexplored.
Methods:
Nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were employed to characterize exosomes derived from MSCs. Flow cytometry analysis was conducted to investigate the function of exosomal miR-125b-5p both in vitro and in vivo. Mouse MC38 tumor models were administrated MSC-derived exosomes containing miR-125b-5p via tail vein injection, with or without the concurrent injection (intraperitoneally, i.p.) of anti-PD-1 antibodies.
Results:
Our results indicated that exosomal miR-125b-5p derived from MSC significantly inhibited the expansion, proliferation and suppressive function of Tregs in vitro. Moreover, we observed a marked reduction in tumor growth in mice treated with exosomal miR-125b-5p. Notably, while anti-PD-1 therapy alone achieved a cure rate of approximately 30% in a mouse model of colon cancer, the combined administration of exosomal miR-125b-5p significantly enhanced the therapeutic efficacy, resulting in a more than two- to three-fold increase in tumor regression in approximately 80% of the treated mice. The underlying cellular mechanism was closely associated with the reduction of tumor-infiltrating Tregs. and the increase of CD8+ cytotoxic T lymphocytes (CTLs).
Conclusions:
In summary, our findings suggest that exosomal miR-125b-5p derived from MSC exerts prominent potential in advancing anti-PD-1 therapy by modulating tumor immune environment. This property of miR-125b-5p may be therapeutically harnessed in human cancers to enhance the efficacy of immunotherapy.
Insights
Mesenchymal stromal/stem cell (MSC)-derived exosomes carrying miR-125b-5p inhibit regulatory T cells (Tregs), enhancing anti-PD-1 cancer immunotherapy efficacy and reducing tumor growth.
Area of Science:
- Immunology
- Cancer Research
- Molecular Biology
Background:
- FoxP3+ regulatory T cells (Tregs) promote tumor immune evasion.
- miR-125b-5p inhibits Tregs by targeting TNFR2 and FoxP3.
- Mesenchymal stromal/stem cell (MSC)-derived exosomes (MSC-EXO) have therapeutic potential in cancer.
Purpose of the Study:
- To investigate the role of MSC-EXO in delivering miR-125b-5p to augment anti-tumor immunotherapy.
- To evaluate the therapeutic potential of exosomal miR-125b-5p in combination with anti-PD-1 therapy.
Main Methods:
- Characterization of MSC-EXO using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM).
- Flow cytometry to assess exosomal miR-125b-5p function in vitro and in vivo.
- Administration of miR-125b-5p-loaded MSC-EXO in MC38 mouse tumor models, with or without anti-PD-1 antibodies.
Main Results:
- Exosomal miR-125b-5p significantly inhibited Treg expansion, proliferation, and suppressive function in vitro.
- Treatment with exosomal miR-125b-5p reduced tumor growth in mice.
- Combination therapy (exosomal miR-125b-5p and anti-PD-1) significantly enhanced tumor regression (80% response rate) compared to anti-PD-1 alone (30% cure rate), by reducing tumor-infiltrating Tregs and increasing CD8+ cytotoxic T lymphocytes (CTLs).
Conclusions:
- Exosomal miR-125b-5p derived from MSC shows significant potential in enhancing anti-PD-1 therapy by modulating the tumor immune microenvironment.
- This miR-125b-5p delivery strategy may be a promising approach to improve immunotherapy efficacy in human cancers.
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