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Functionalized Poly(ethylene Glycol) Diacrylate Scaffolds for In Situ Immunomodulation of Dendritic Cells Targeting
Neha Dalal1, Hemavathi Dhandapani1, Arvind Ingle2
1Department of Bioscience and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
Abstract:
Various immunotherapeutic strategies are being developed to fight cancer, which is one of the leading causes of mortality. Dendritic cells (DCs), being professional antigen-presenting cells, after efficient manipulation with tumor-associated antigens, can lead to effective T-cell recruitment and activation at the tumor site, resulting in cytotoxic T-cell-mediated cancer cell killing. To circumvent the inefficiencies of ex vivo DC modification and patient infusion, an alternative strategy involving in situ DC activation has been explored here. Here, the vaccine components are tumor lysates, as antigens, and polyinosinic:polycytidylic acid (poly(I:C)), a toll-like receptor-3 (TLR3) agonist, as an adjuvant. Our in vitro studies demonstrate that complexing poly(I:C) with a carrier molecule, chitosan, enhances its stability and accessibility to TLR3 in the DC endosomal membrane. Material-based localized delivery of immunomodulatory factors is known to improve their stability and reduce their off-target side effects. Here, PEGDA-PLL-based macroporous scaffolds allow easy recruitment of host cells, thereby enabling effective interaction between the vaccine components loaded on them and the infiltrating immune cells. The vaccine components present in the scaffold facilitate efficient DC activation and migration, leading to subsequent T-cell activation and antitumor response, as shown by our in vivo studies.
Insights
This study explores an in situ cancer vaccine using tumor lysates and poly(I:C) delivered via scaffolds. This approach enhances dendritic cell activation and T-cell response for effective antitumor immunity.
Area of Science:
- Immunology
- Biomaterials Science
- Oncology
Background:
- Cancer immunotherapy aims to harness the immune system against tumors.
- Dendritic cells (DCs) are crucial for initiating anti-tumor T-cell responses.
- Current ex vivo DC modification methods face challenges in efficiency and patient delivery.
Purpose of the Study:
- To develop an in situ cancer vaccine strategy for improved dendritic cell activation.
- To evaluate the efficacy of tumor lysates combined with poly(I:C) as an adjuvant.
- To assess the role of chitosan complexation and macroporous scaffolds in vaccine delivery and immune response.
Main Methods:
- In vitro studies on poly(I:C) complexation with chitosan for enhanced DC targeting.
- Development of PEGDA-PLL-based macroporous scaffolds for localized vaccine delivery.
- In vivo evaluation of the scaffold-based vaccine's ability to induce DC migration, T-cell activation, and anti-tumor effects.
Main Results:
- Chitosan complexation improved poly(I:C) stability and accessibility to Toll-like receptor 3 (TLR3).
- PEGDA-PLL scaffolds effectively recruited host cells and facilitated interaction with vaccine components.
- In vivo studies demonstrated scaffold-mediated DC activation, migration, T-cell activation, and significant anti-tumor responses.
Conclusions:
- In situ vaccination using tumor lysates and poly(I:C) delivered via macroporous scaffolds is a promising cancer immunotherapy strategy.
- Material-based delivery enhances vaccine stability, targeting, and reduces off-target effects.
- This approach effectively stimulates dendritic cell and T-cell-mediated anti-tumor immunity.
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