Sandra Clara-Trujillo, Alba Ortuño-Bernal, Elena Lucena-Sánchez, Francisco J.Hicke, Andrea Escudero, Sandra Pradana-López, Paula Díez, Alba García-Fernández, Ramón Martínez Máñez.
Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat de València–Universitat Politècnica de València, Camino de Vera s/n, 46022, Valencia, Spain.
CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III.
Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Valencia, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, Valencia Spain.
Unidad Mixta de Investigación en Nanomedicina y Sensores. Universitat Politècnica de València, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia Spain.
Cytotoxic T cells (CTL) play a pivotal role in recognizing and eliminating tumor cells. However, their effectiveness can be compromised by immune escape mechanisms, leading to cancer progression. Here, we present a nanoplatform able to restore compromised immunological synapses. The nanodevice consists of a Janus mesoporous silica-Au nanoparticle functionalized with specific binding sites in opposite faces (J-pHLIP-PD1) for cancer cells (targeted through the membrane-intercalating peptide pHLIP) and for CTL (targeted through the PD1 receptor).
J-pHLIP-PD1 nanoparticles effectively bind the surface of tumor cells (Sk-Mel-103 cells). Using a transwell co-culture system, we confirmed the ability of J-pHLIP-PD1 to facilitate binding between T-lymphocytes (Jurkat T-cells) and tumor cells. Furthermore, in vitro evaluation of human primary CTL cytotoxicity against Sk-Mel-103 demonstrated increased efficacy with the complete J-pHLIP-PD1 nanodevice compared to control groups (J-PHLIP, J-PD1, and free PD1). Finally, therapeutic potential of J-pHLIP-PD1 is demonstrated in a metastatic melanoma cancer model. The treatment with J-pHLIP-PD1 produces a significant decrease in metastatic burden accompanied by an increased presence of cytotoxic T cells. These findings underscore the potential of J-pHLIP-PD1 as a promising strategy for enhancing immunotherapeutic approaches.
Acknowledgments
This work was supported by the European Research Council (ERC) via Advanced Grant (101052997, EDISON). The authors thank the Spanish Government (project PID2021-126304OB-C4) by MCIN/ AEI /10.13039/501100011033/ and by European Regional Development Fund – A way of doing Europe. This study was also supported by the Generalitat Valenciana (project PROMETEO CIPROM/2021/007). This study forms part of the Advanced Materials program (MFA/2022/049) and was supported by MCIN with funding from European Union NextGenerationEU (PRTR-C17.I1). This work was supported by the CIBER Consorcio Centro de Investigación Biomédica en Red- (CB06/01/2012), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación.E.L-S thanks her FPU fellowship funded by MINECO (FPU18/06539). F.J.H thanks MIU for his FPU grant (FPU20/06021).
sanclatr@doctor.upv.es
