2. Academic Validation
  3. Myeloid leukemia-derived galectin-1 downregulates CAR expression to hinder cytotoxicity of CAR T cells

Myeloid leukemia-derived galectin-1 downregulates CAR expression to hinder cytotoxicity of CAR T cells

  • J Transl Med. 2024 Jan 6;22(1):32. doi: 10.1186/s12967-023-04832-x.
Chuo Li # 1 2 3,  Shiyu Zuo # 1 2 3,  Lingling Shan 1 2,  Huifang Huang 4,  Haidong Cui 5,  Xiaoming Feng 6 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
  • 2 Tianjin Institutes of Health Science, Tianjin, 301600, China.
  • 3 Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
  • 4 Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China. huanghuif@126.com.
  • 5 Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China. cuihaidong79@163.com.
  • 6 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. fengxiaoming@ihcams.ac.cn.
  • 7 Tianjin Institutes of Health Science, Tianjin, 301600, China. fengxiaoming@ihcams.ac.cn.
  • 8 Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China. fengxiaoming@ihcams.ac.cn.
  • # Contributed equally.
PMID: 38184596 DOI: 10.1186/s12967-023-04832-x
Abstract

Background: Chimeric antigen receptor (CAR) T cells have shown significant activity in B-lineage malignancies. However, their efficacy in myeloid leukemia has not been successful due to unclear molecular mechanisms.

Methods: We conducted in vitro and in vivo experiments to investigate whether myeloid leukemia cells directly induce CAR down-regulation. Furthermore, we designed a CD33 CARKR in which all lysines in the cytoplasmic domain of CAR were mutated to arginine and verified through in vitro experiments that it could reduce the down-regulation of surface CARs and enhance the killing ability. Transcriptome Sequencing was performed on various AML and ALL cell lines and primary samples, and the galectin-1-specific inhibitory peptide (anginex) successfully rescued the killing defect and T-cell activation in in vitro assays.

Results: CAR down-regulation induced by myeloid leukemia cells under conditions of low effector-to-tumor ratio, which in turn impairs the cytotoxicity of CAR T cells. In contrast, lysosomal degradation or actin polymerization inhibitors can effectively alleviate CAR down-regulation and restore CAR T cell-mediated anti-tumor functions. In addition, this study identified Galectin-1 as a critical factor used by myeloid leukemia cells to induce CAR down-regulation, resulting in impaired T-cell activation.

Conclusion: The discovery of the role of Galectin-1 in cell surface CAR down-regulation provides important insights for developing strategies to restore anti-tumor functions.

Keywords

AML; CAR down-regulation; Galectin-1.

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Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P1592
    99.44%, Galectin-3 Binding Peptide
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