Precision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironment

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Publication . Carreira, Barbara; Ferreira, Helena Isabel Fialho Florindo Roque; Satchi-Fainaro, Ronit

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.

2023-09Tese de doutoramento

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Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment

Publication . Acúrcio, Rita C; Pozzi, Sabina; Carreira, Barbara; Pojo, Marta; Gómez-Cebrián, Nuria; Casimiro, Sandra; Fernandes, Adelaide; Barateiro, Andreia; Farricha, Vitor; Soares Do Brito, Joaquim; Leandro, P; Salvador, Jorge A. R.; Graca, Luis; Puchades-Carrasco, Leonor; Costa, Luis; Satchi-Fainaro, Ronit; Guedes, R. C.; Florindo, Helena F

Background: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents. Methods: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function. Results: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy. Conclusions: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.

2022Artigo científico

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/131969/2017