Immune isolation-enabled nanoencapsulation of donor T cells: a promising strategy for mitigating GVHD and treating AML in preclinical models

• Published in: Journal for immunotherapy of cancer 2024-09, Vol.12 (9), p.e008663
• Main Authors: Mei, Dan, Xue, Ziyang, Zhang, Tianjing, Yang, Yining, Jin, Lin, Yu, Qianqian, Hong, Jian, Zhang, Xianzheng, Ge, Jinru, Xu, Li, Wang, Han, Zhang, Ziwei, Zhao, Yuchen, Zhai, Yuanfang, Tao, Qianshan, Zhai, Zhimin, Li, Qingsheng, Li, Hongxia, Zhang, Lingling
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antigens; Cell growth; Clinical/Translational Cancer Immunotherapy; Disease Models, Animal; Graft versus host disease; Graft versus host disease - GVHD; Graft versus leukemia; Graft vs Host Disease - immunology; Graft vs Leukemia Effect; Humans; Leukemia; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - therapy; Ligands; Lymphocytes; Mice; Nanocapsules - chemistry; Nanoparticle; Original Research; Reagents; Synapses; T cell; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-008663

BackgroundIn allogeneic-hematopoietic stem cell transplantation for acute myeloid leukemia (AML), donor T cells combat leukemia through the graft-versus-leukemia (GVL) effect, while they also pose a risk of triggering life-threatening graft-versus-host disease (GVHD) by interacting with recipient cells. The onset of GVHD hinges on the interplay between donor T cells and recipient antigen-presenting cells (APCs), sparking T-cell activation. However, effective methods to balance GVHD and GVL are lacking.MethodsIn our study, we crafted nanocapsules by layering polycationic aminated gelatin and polyanionic alginate onto the surface of T cells, examining potential alterations in their fundamental physiological functions. Subsequently, we established an AML mouse model and treated it with transplantation of bone marrow cells (BMCs) combined with encapsulated T cells to investigate the GVL and anti-GVHD effects of encapsulated T cells. In vitro co-culture was employed to probe the effects of encapsulation on immune synapses, co-stimulatory molecules, and tumor-killing pathways.ResultsTransplantation of BMCs combined with donor T cells selectively encapsulated onto AML mice significantly alleviates GVHD symptoms while preserving essential GVL effects. Encapsulated T cells exerted their immunomodulatory effects by impeding the formation of immune synapses with recipient APCs, thereby downregulating co-stimulatory signals such as CD28-CD80, ICOS-ICOSL, and CD40L-CD40. Recipient mice receiving encapsulated T-cell transplantation exhibited a marked increase in donor Ly-5.1-BMC cell numbers, accompanied by unaltered in vivo expression levels of perforin and granzyme B. While transient inhibition of donor T-cell cytotoxicity in the tumor microenvironment was observed in vitro following single-cell nanoencapsulation, subsequent restoration to normal antitumor activity ensued, attributed to selective permeability of encapsulated vesicle shells and material degradation. Moreover, the expression of apoptotic proteins and FAS-FAS ligand pathway at normal levels was still observed in leukemia tumor cells.ConclusionsEncapsulated donor T cells effectively mitigate GVHD while preserving the GVL effect by minimizing co-stimulatory signaling with APCs through early immune isolation. Subsequent degradation of nanocapsules restores T-cell cytotoxic efficacy against AML cells, mediated by cytotoxic pathways. Using transplant-encapsulated T cells offers a promising strategy to suppres