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Precision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironment
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Resumo(s)
Despite the remarkable efficiency of immune checkpoint modulators against metastatic melanoma, only a small percentage of patients respond to these therapies. Among the responders, clinical trials report immune-mediated side effects and disease relapse. Immune checkpoint inhibitors inefficiency is being attributed to tumor-related immunosuppression pathways and limited infiltration of effector T cells. To overcome these limitations, new synergistic strategies are urgently needed.
To that end, we focused on the development of a precision nanosystem based therapy to specifically target dendritic cells (DC) and successfully modulate melanoma-immune cell interactions by expanding the range of targeted cells in a site-specific manner. For this purpose, we designed, synthesized, and characterized poly(lactic acid) and poly(lactic-co-glycol) (PLA/PLGA)-based nano-vaccines using mannose-grafted polymers to deliver combinations of melanoma neoantigen, toll-like receptor ligands, and regulators of the PD-1/PD-L1 pathway. These cancer nano-vaccinesamplified antitumor immune responses by increasing tumor-associated antigen recognition, processing, and presentation to effector T cells. The polymeric nanoparticles presented spherical shape with an average diameter of 180 nm, displaying a narrow polydispersity index, near-neutral surface charge, and high loadings of the immune regulators. Both subcutaneous and intranasal immunizations induced the activation and maturation of DC within draining lymph nodes and triggered the systemic activation of neoantigen-specific cytotoxic T cells.
Treatment with the combination of the therapeutic nano-vaccineswith PD-1/PD-L1 modulators in vivo led to increased tumor inhibition in orthotopic primary melanoma-bearing mice, with minimal systemic toxicity. The combination of the nano-vaccine with the PD-L1 monoclonal antibody was the most effective, with maximal tumor growth inhibition, translated into extensive infiltration of cytotoxic CD8+ T cells into the tumor microenvironment and reduced expression of immunosuppressor cells. At the metastatic disease, followed by primary tumor resection, the intranasal immunization of the therapeutic nano-vaccine combined with the PD-L1 immune checkpoint inhibitor led to the prevention of melanoma brain metastases. The combination strategy led to 100% survival at 52 days followed intracranial tumor inoculation and recapitulation into a T-cell inflamed brain tumor microenvironment. Altogether, the synergy between the nano-vaccine and the PD-L1 antibody provides essential insights to devise alternative combination regimens to improve the efficacy of immune checkpoint inhibitors in metastatic melanoma, thus opening a new line for polymeric nano-vaccines as a potential tool to advance clinical response to advanced melanoma.
Descrição
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Nanovacinas imunoterapia intranasal PD-L1 metástases cerebrais de melanoma nano-vaccines immunotherapy intranasal melanoma brain metástases