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Updated: Jun 3, 2025
Generation of Induced Regulatory T Cells from Primary Human Naïve and Memory T Cells
Published on: April 16, 2012
PD1-Targeted Transgene Delivery to Treg Cells
Vladislav A Zhuchkov1,2, Yulia E Kravchenko1, Elena I Frolova1
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
Abstract:
Achieving the precise targeting of lentiviral vectors (LVs) to specific cell populations is crucial for effective gene therapy, particularly in cancer treatment where the modulation of the tumor microenvironment can enhance anti-tumor immunity. Programmed cell death protein 1 (PD-1) is overexpressed on activated tumor-infiltrating T lymphocytes, including regulatory T cells that suppress immune responses via FOXP3 expression. We developed PD1-targeted LVs by incorporating the anti-PD1 nanobody nb102c3 into receptor-blinded measles virus H and VSV-Gmut glycoproteins. We assessed the retargeting potential of nb102c3 and evaluated transduction efficiency in activated T lymphocytes. FOXP3 expression was suppressed using shRNA delivered by these LVs. Our results demonstrate that PD1-targeted LVs exerted pronounced tropism towards PD1+ cells, enabling the selective transduction of activated T lymphocytes while sparing naive T cells. The suppression of FOXP3 in Tregs reduced their suppressive activity. PD1-targeted glycoprotein H provided greater specificity, whereas the VSV-Gmut, together with the anti-PD1 pseudoreceptor, achieved higher viral titers but was less selective. Our study demonstrates that PD1-targeted LVs may offer a novel strategy to modulate immune responses within the tumor microenvironment with the potential for developing new therapeutic strategies aimed at enhancing anti-tumor immunity.
Insights
Researchers developed targeted lentiviral vectors (LVs) to deliver gene therapy to specific immune cells. These PD-1 targeted LVs selectively target and modify T cells, offering a new approach to enhance anti-tumor immunity in cancer treatment.
Area of Science:
- Immunology
- Gene Therapy
- Oncology
Background:
- Precise targeting of lentiviral vectors (LVs) is essential for effective gene therapy, especially in cancer for modulating the tumor microenvironment.
- Programmed cell death protein 1 (PD-1) is upregulated on tumor-infiltrating T lymphocytes, including regulatory T cells (Tregs) that suppress immune responses.
Purpose of the Study:
- To develop PD-1 targeted LVs for selective gene delivery to PD-1 expressing cells.
- To evaluate the efficacy of these LVs in modulating T cell responses and suppressing FOXP3 expression in Tregs.
Main Methods:
- Engineered LVs by incorporating an anti-PD-1 nanobody (nb102c3) into modified viral glycoproteins (measles virus H and VSV-Gmut).
- Assessed LV retargeting specificity and transduction efficiency in activated T lymphocytes.
- Delivered shRNA via LVs to suppress FOXP3 expression in Tregs.
Main Results:
- PD-1 targeted LVs demonstrated tropism towards PD-1+ cells, selectively transducing activated T lymphocytes while sparing naive T cells.
- Suppression of FOXP3 in Tregs reduced their immune suppressive activity.
- PD-1 targeted glycoprotein H offered higher specificity, while VSV-Gmut achieved higher viral titers but with less selectivity.
Conclusions:
- PD-1 targeted LVs represent a novel strategy for modulating immune responses within the tumor microenvironment.
- This approach holds potential for developing new therapeutic strategies to enhance anti-tumor immunity.
