Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy Blaya Cánovas, José Lucas Griñán Lisón, Carmen Blancas López-Barajas, María Isabel Marchal Corrales, Juan Antonio Ramírez Tortosa, César Luis López Tejada, Araceli Benabdellah, Karim Cortijo Gutiérrez, Marina Cano Cortes, María Victoria Graván, Pablo Navarro Marchal, Saul Abenhamar Gómez-Morales, Jaime Calahorra, Jesús Rodríguez-González, Carlos J. Gallart Aragón, Tania Sánchez Martín, Rosario María Granados Principal, Sergio Biomimetic nanoparticles Immune checkpoint Immune evasion Immunotherapy PD1 PDL1 Patient-derived xenograft T-cell exhaustion Triple-negative breast cancer This work was funded by Instituto de Salud Carlos III (grants PI19/01533, CP19/00029 to S.G.-P.), Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (grant P29/22/02 to S.G.-P.), by MCIN/AE (grant RTI2018.101309B-C22 and PID2022-140151OB-C22 funded by MCIN/AEI https://doi.org/10.13039/501100011033 and by the European Union NextGenerationEU/PRTR to J.A.M.), the Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963 to J.A.M.), the European Regional Development Fund (European Union), Fundación Científica Asociación Española Contra el Cáncer, Junta Provincial de Jaén (AECC) (grant PRDJA19001BLAY to J.L.B.-C.,), Proyectos Intramurales ibs.GRANADA (grant INTRAIBS-2021-09 to C.G.-L.), Junta de Andalucía, Plan Andaluz de Investigación, Desarrollo e Innovación (grant POSTDOC_21_638 to C.G.-L.), Ministerio de Ciencia, Innovación y Universidades (grant FPU19/04450 to A.L.-T.), Junta de Andalucía, Consejería de Transformación Económica, Industria, Conocimiento y Universidades (grant DOC_01686 to J.C.). Background: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. Methods: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. Results: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. Conclusions: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT. 2024-09-19T06:37:49Z 2024-09-19T06:37:49Z 2024-05-09 journal article Blaya-Cánovas, J.L., Griñán-Lisón, C., Blancas, I. et al. Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy. Mol Cancer 23, 83 (2024). https://doi.org/10.1186/s12943-024-01997-x https://hdl.handle.net/10481/94672 10.1186/s12943-024-01997-x eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional BMC