Modified dendritic cell-derived exosomes activate both NK cells and T cells through the NKG2D/NKG2D-L pathway to kill
Zhuanyun Du1, Zhenglan Huang1, Xi Chen2
1Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, China.
Background:
Tyrosine kinase inhibitors have achieved quite spectacular advances in the treatment of chronic myeloid leukemia (CML), but disease progression and drug resistance that related to the T315I mutation, remain major obstacles. Dendritic cell-derived exosomes (Dex) induce NK cell immunity, but have yet to achieve satisfactory clinical efficacy. An approach to potentiate antitumor immunity by inducing both NK- and T-cell activation is urgently needed. Retinoic acid early inducible-1γ (RAE-1γ), a major ligand of natural killer group 2 member D (NKG2D), plays an important role in NK-cell and T-lymphocyte responses. We generated RAE-1γ enriched CML-specific Dex (CML-RAE-1γ-Dex) from dendritic cells (DCs) pulsed with lysates of RAE-1γ-expressing CML cells or T315I-mutant CML cells, aiming to simultaneously activate NK cells and T lymphocytes.
Methods:
We generated novel CML-RAE-1γ-Dex vaccines, which expressed RAE-1γ, and were loaded with CML tumor cell lysates. NK cells or T lymphocytes were coincubated with CML-RAE-1γ-Dex vaccines. Flow cytometry was performed to evaluate the activation and proliferation of these immune cells. Cytokine production and cytotoxicity toward CML cells with or without the T315I mutation were detected by ELISPOT, ELISA and LDH assays. CML models induced by BCR-ABL or BCR-ABLT315I were used to determine the immunological function of Dex in vivo.
Results:
Herein, CML-RAE-1γ-Dex were prepared. CML-RAE-1γ-Dex effectively enhanced the proliferation and effector functions of NK cells, CD4+ T cells and CD8+ T cells, which in turn produced strong anti-CML efficacy in vitro. Moreover, CML-RAE-1γ-Dex-based immunotherapy inhibited leukemogenesis and generated durable immunological memory in CML mouse models. Similar immune responses were also observed with imatinib-resistant CML cells carrying the T315I mutation.
Conclusions:
This approach based on CML-RAE-1γ-Dex vaccines may be a promising strategy for CML treatment, especially for cases with the T315I mutation.
Insights
This study developed novel RAE-1γ-enriched exosomes from chronic myeloid leukemia (CML) cells to activate both NK and T cells. These CML-RAE-1γ-Dex vaccines show promise for treating CML, including drug-resistant T315I mutations.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML) but face challenges with drug resistance, particularly the T315I mutation.
- Dendritic cell-derived exosomes (Dex) can induce NK cell immunity but require enhancement for clinical efficacy.
- Activating both NK and T cells is crucial for potentiating antitumor immunity against CML.
Purpose of the Study:
- To develop RAE-1γ-enriched CML-specific Dex (CML-RAE-1γ-Dex) to simultaneously activate NK cells and T lymphocytes.
- To evaluate the therapeutic potential of CML-RAE-1γ-Dex in preclinical CML models, including those with T315I mutations.
Main Methods:
- Generation of CML-RAE-1γ-Dex vaccines by pulsing dendritic cells with CML cell lysates expressing RAE-1γ.
- Coincubation of NK cells and T lymphocytes with CML-RAE-1γ-Dex to assess immune cell activation, proliferation, cytokine production, and cytotoxicity.
- In vivo evaluation of CML-RAE-1γ-Dex immunotherapy in BCR-ABL and BCR-ABLT315I induced CML mouse models.
Main Results:
- CML-RAE-1γ-Dex effectively enhanced the proliferation and effector functions of NK, CD4+, and CD8+ T cells in vitro.
- These activated immune cells demonstrated potent anti-CML efficacy against both wild-type and T315I-mutant CML cells.
- In vivo studies showed that CML-RAE-1γ-Dex-based immunotherapy inhibited leukemogenesis and established durable immunological memory in CML mouse models.
Conclusions:
- CML-RAE-1γ-Dex vaccines represent a promising strategy for CML treatment.
- This approach is particularly relevant for managing CML cases that exhibit resistance due to the T315I mutation.
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