Transformable prodrug nanoplatform via tumor microenvironment modulation and immune checkpoint blockade potentiates immunogenic cell death mediated cancer immunotherapy

by Selleckchem | Aug 04 2023

Rationale: Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance.

Methods: Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist (DPPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core (DPPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part.

Results: DPPA-TRPP/Tab reassembled into a micellar structure in vivo with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by DPPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. In vivo results indicated that DPPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response.

Conclusion: The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform.

Comments:

The rationale of the study is to address the limitations of chemoimmunotherapy in cancer treatment, specifically the high levels of reactive oxygen species (ROS), the presence of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), and immune checkpoints that enable cancer cells to evade the immune system.

The researchers developed a novel nanoplatform called the TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform. This nanoplatform consisted of a D-peptide antagonist (DPPA-1) of programmed death ligand-1 (PD-L1) conjugated onto the surface and talabostat mesylate (Tab), a fibroblast activation protein inhibitor, encapsulated in the watery core (DPPA-TRPP/Tab). The chain of the nanoplatform was conjugated with doxorubicin (DOX), which served as an immunogenic cell death (ICD) inducer and hydrophobic component.

The results showed that DPPA-TRPP/Tab underwent reassembly into a micellar structure in the TME, modulating the TME by inhibiting CAFs through Tab release. It also consumed ROS using 2,2'-diselanediylbis(ethan-1-ol), blocked immune checkpoints via DPPA-1, and induced immunogenic cell death through DOX release. The nanoplatform resolved the challenge of delivering hydrophilic Tab for CAF inhibition and hydrophobic DOX for ICD by reassembling in the weakly acidic TME through polymersome-micelle transformation.

In vivo experiments demonstrated that DPPA-TRPP/Tab improved tumor accumulation, suppressed CAF formation, downregulated regulatory T cells, and promoted T lymphocyte infiltration. In mice, it achieved a 60% complete tumor regression ratio and induced a long-term immune memory response.

The study suggests that the developed DPPA-TRPP/Tab nanoplatform has the potential to enhance tumor eradication by combining multiple therapeutic strategies in a single smart polymeric nanoplatform. This "all-in-one" approach could overcome the limitations of chemoimmunotherapy and provide a promising strategy for cancer treatment.