Abstract
Immune checkpoint inhibitors become a standard therapy for malignant melanoma. As immune checkpoint inhibitor monotherapies proved to have limited efficacy in significant portion of patients, it is envisaged that combination with other therapeutic modalities may improve clinical outcomes. We investigated the effect of combining photodynamic therapy (PDT) and TLR5 agonist flagellin-adjuvanted tumor-specific peptide vaccination (FlaB-Vax) on the promotion of PD-1 blockade-mediated melanoma suppression using a mouse B16-F10 implantation model. Using a bilateral mouse melanoma cancer model, we evaluated the potentiation of PD-1 blockade by the combination of peritumoral FlaB-Vax delivery and PDT tumor ablation. A photosensitizing agent, pheophorbide A (PhA), was used for laser-triggered photodynamic destruction of the primary tumor. The effect of combination therapy in conjunction with PD-1 blockade was evaluated for tumor growth and survival. The effector cytokines that promote the activation of CD8+ T cells and antigen-presenting cells in tumor tissue and tumor-draining lymph nodes (TDLNs) were also assayed. PDT and FlaB-Vax combination therapy induced efficacious systemic antitumor immune responses for local and abscopal tumor control, with a significant increase in tumor-infiltrating effector memory CD8+ T cells and systemic IFNγ secretion. The combination of PDT and FlaB-Vax also enhanced the infiltration of tumor antigen-reactive CD8+ T cells and the accumulation of migratory CXCL10-secreting CD103+ dendritic cells (DCs) presumably contributing to tumor antigen cross-presentation in the tumor microenvironment (TME). The CD8+ T-cell-dependent therapeutic benefits of PDT combined with FlaB-Vax was significantly enhanced by a PD-1-targeting checkpoint inhibitor therapy. Conclusively, the combination of FlaB-Vax with PDT-mediated tumor ablation would serve a safe and feasible combinatorial therapy for enhancing PD-1 blockade treatment of malignant melanoma.
Highlights
Melanoma is the most aggressive and invasive form of skin cancer and can metastasize to virtually any organ of the body: it has very low survival rate and easy relapse tendency
The photodynamic therapy (PDT) + Vax combination induced significantly enhanced abscopal immunity suppressing tumor growth in the distant site (Figure 1D). These results suggest that the combination of PDT and FlaB-Vax exerted a cooperative effect on inducing tumor-specific immune responses, which may possibly be further potentiated by immune checkpoint inhibitors (ICIs) therapy
CXCL10-secreting CD103+ cells in the combination group (Supplementary Figure S2). These results suggest that the tumor-specific CD8+ T cell infiltration in tumor microenvironment (TME) and tumor-draining lymph nodes (TDLNs) would have been mediated by CXCL10-secreting CD103+ dendritic cells (DCs), which should have induced tumor antigen-specific CD8+ cytotoxic T lymphocyte (CTL) through tumor antigen cross-presentation
Summary
Melanoma is the most aggressive and invasive form of skin cancer and can metastasize to virtually any organ of the body: it has very low survival rate and easy relapse tendency. PDT has been shown to release tumor antigens and immunogenic damage-associated molecular patterns (DAMPs) from affected tumor cells [8] By combining these immunologic effects, PDT creates a favorable microenvironment for tumor antigen expansion and antigen-presenting cell activation [9]. The PDT-mediated TME modulation should create significantly “hotter” immunological niche where ICIs and tumor killing immune cells will become more active. It has been well demonstrated that cancer vaccines employing tumor-associated antigens (TAAs) can induce substantial tumor-specific immunities and epitope expansion [19], which should be an advantage over other modalities enhancing pre-existing immunity nonspecifically, such as ICI or cytokine therapies [20]. Compared with PDT alone, the combination regimen released a higher amount of CXCL10 cytokines that would contribute to more effective CD8+ T cell infiltration and antigen cross-presentation by CD103+ CD11C+ DC subsets
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