PDL-1/PDL-2 blockade in mice dendritic cells by RNAi techniques to induce antitumor immunity
Saeed Daneshmandi1, Ali Akbar Pourfathollah1, Mohammad Hossein Karimi2
1Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Aim:
We provided potent dendritic cells (DCs) for induction of stronger antitumor immune responses.
Materials & Methods:
Using siRNA and shRNA systems, PDL-1 and PDL-2 were knocked down and then DC in vitro and in vivo properties were evaluated.
Results:
Mild suppression of PDL-1/PDL-2 molecules was accompanied by appropriate expression of DCs co-stimulatory molecules and release of proinflammatory cytokines. In vitro T-cell engagement induced the proliferation and secretion of Th1 cytokines. Injection of DCs to a 4T1 mice model induced intratumor CD8(+) infiltrating lymphocytes, splenocytes expansion, Th1 cytokine profile shift, and a mild drift to tumor growth inhibition and mice survival.
Conclusion:
Manipulated DCs induced significant antitumor immunity, but this subject needs further evaluation in different animals.
Insights
Researchers engineered dendritic cells (DCs) by reducing PDL-1/PDL-2 expression, enhancing their ability to stimulate antitumor immune responses and T-cell activity in preclinical models.
Area of Science:
- Immunology
- Cancer Biology
- Cell Therapy
Background:
- Dendritic cells (DCs) are crucial for initiating adaptive immune responses.
- Immune checkpoints, such as PD-1/PD-L1, regulate T-cell activity and can be exploited by tumors.
- Modulating DC function holds potential for cancer immunotherapy.
Purpose of the Study:
- To engineer dendritic cells (DCs) with enhanced antitumor properties.
- To investigate the impact of PD-L1 and PD-L2 knockdown on DC function.
- To evaluate the efficacy of manipulated DCs in a preclinical cancer model.
Main Methods:
- Utilized siRNA and shRNA systems to achieve knockdown of PD-L1 and PD-L2 in DCs.
- Assessed in vitro and in vivo properties of engineered DCs.
- Evaluated DC-mediated immune responses in a 4T1 mouse tumor model.
Main Results:
- PD-L1/PD-L2 knockdown resulted in appropriate co-stimulatory molecule expression and pro-inflammatory cytokine release.
- In vitro, engineered DCs promoted T-cell proliferation and Th1 cytokine secretion.
- In vivo, DC injection led to increased intratumoral CD8+ T cells, splenocyte expansion, a Th1 shift, and modest tumor growth inhibition and survival improvement.
Conclusions:
- Engineered DCs demonstrated the capacity to induce significant antitumor immunity.
- Further investigation in diverse animal models is warranted to fully elucidate the therapeutic potential.
