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IL-7 promotes CD19-directed CAR-T cells proliferation through miRNA-98-5p by targeting CDKN1A
Li-Rong Yang1, Lin Li2, Ming-Yao Meng2
1Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Department of Oncology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China.
International Immunopharmacology
|September 27, 2023
Summary
Interleukin-7 (IL-7) enhances chimeric antigen receptor T-cell (CAR-T) proliferation against CD19+ cancers. This occurs via miRNA-98-5p targeting CDKN1A, improving CAR-T therapy efficacy.
Area of Science:
- Immunology
- Cell Biology
- Cancer Therapy
Background:
- Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 shows promise for B-cell leukemia and lymphoma.
- Challenges remain, including frequent relapses and incomplete remission, necessitating improvements in CAR-T cell proliferation, cytotoxicity, exhaustion, and infiltration.
- Interleukin-7 (IL-7) is known to enhance CAR-T memory characteristics, but the underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of microRNAs (miRNAs) in IL-7-mediated activation of anti-CD19 CAR-T cells.
- To elucidate the specific mechanisms by which IL-7 enhances CAR-T cell function.
- To explore the potential application of IL-7 in improving CAR-T cell production for enhanced cancer treatment.
Main Methods:
- Utilized established 3rd generation anti-CD19 CAR-T cells.
- Assessed the effects of IL-7 on CAR-T cell proliferation, CD4+ CAR+ cell ratio, and cell cycle (S phase).
- Evaluated in vivo anti-tumor efficacy using a NAMALWA xenograft model.
- Quantified the expression of CDKN1A and miRNA-98-5p in IL-7-stimulated CAR-T cells.
- Investigated the association between CDKN1A and miRNA-98-5p.
Main Results:
- IL-7 significantly increased the proliferation of anti-CD19 CAR-T cells and the proportion of CD4+ CAR+ cells, promoting cell cycle progression into the S phase.
- IL-7-stimulated CAR-T cells demonstrated enhanced tumoricidal efficiency in the NAMALWA xenograft model.
- IL-7 treatment led to decreased CDKN1A expression and increased miRNA-98-5p expression in CAR-T cells.
- A significant association was identified between CDKN1A expression and miRNA-98-5p levels.
Conclusions:
- IL-7 enhances anti-CD19 CAR-T cell proliferation and anti-tumor activity.
- This enhancement is mediated by the IL-7-induced upregulation of miRNA-98-5p, which targets and downregulates CDKN1A expression.
- The findings suggest a novel mechanism for IL-7 in CAR-T cell activation and provide a basis for applying IL-7 in CAR-T cell production strategies.
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