Summary of this article

1. Pancreatic cancer has a low response rate to chemotherapy or immunotherapy. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for the treatment of unresectable pancreatic cancer, the immunosuppressive tumor microenvironment of this tumor type allows tumor recurrence. Therefore, enhancing endogenous adaptive anti-tumor immunity is crucial to improve the outcome of ablation therapy and post-ablation immunotherapy.

2. Here, we present a hydrogel microsphere vaccine that enhances the anticancer immune response after ablation by releasing FLT3L and CD40L at the relatively low pH of the tumor bed. The vaccine promotes the migration of tumor-resident type 1 conventional dendritic cells (cDC1) to tumor-draining lymph nodes (TdLNs), thereby initiating a cDC1-mediated antigen cross-presentation cascade that enhances endogenous CD8+ T cell responses.

3. In the orthotopic pancreatic cancer model in male mice, it was found that the hydrogel microsphere vaccine transformed the immune cold tumor microenvironment into a hot environment in a safe and effective manner, thereby significantly improving the survival rate and inhibiting the development of distant metastatic tumors. grow.

Highlights of this article

1. Developed an injectable hydrogel microsphere vaccine that can stimulate the cDC1-mediated antigen cross-presentation cascade, thereby amplifying the anti-tumor immunity of endogenous CD8+ T cells.

2. Combining the hydrogel microsphere vaccine with irreversible electroporation (IRE) ablation effectively inhibited the progression and metastasis of pancreatic cancer and significantly increased the survival of mice.

3. Using the Cas9 plasmid library to target the PD-L1 gene reduces the drug resistance of tumor cells to immune checkpoints and enhances the effect of immunotherapy.

Graphic reference

Figure 1: The cDC1-activated hydrogel microsphere vaccine was used as a general immune amplifier to expand the cDC1/CD8+ T cell anti-tumor axis after ablation therapy.

Figure 2: Preparation and in vitro functional verification of hydrogel microsphere vaccines.

Figure 3: Irreversible Electroporation Ablation Induces Immune Reconstitution in Pancreatic Cancer.

Figure 4: Hydrogel microsphere vaccine amplifies the recruitment, activation, and migration of CD103+CD11b−cDC1s.

Figure 5: Efficacy of hydrogel microsphere vaccine combined with IRE ablation in the treatment of pancreatic cancer.

Figure 6: Activated CD8+ T cells play a key role in the in vitro effects induced by combination therapy.

Figure 7: Depletion of CD8+ T cells in vivo or blockade of MHC-I impairs in vitro effects induced by combined IRE and hydrogel vaccine therapy.

Summarize

- Introduces a novel hydrogel microsphere vaccine that can be injected locally after tumor ablation, releasing cytokines that promote dendritic cell (cDC1) recruitment and activation, and a Cas9 plasmid that inhibits tumor immune checkpoints.
- Demonstrated that hydrogel microsphere vaccines can effectively enhance cDC1-mediated antigen cross-presentation, thereby activating and expanding tumor-specific CD8+ T cells to form a powerful anti-tumor immunity.
- Demonstrated that a hydrogel microsphere vaccine combined with irreversible electroporation ablation significantly delayed tumor recurrence and metastasis in a mouse model of pancreatic cancer and improved survival in mice, demonstrating the utility of this strategy in pancreatic cancer therapy potential.