The CD226‐ERK1/2‐LAMP1 pathway is an important mechanism for Vγ9Vδ2 T cell cytotoxicity against chemotherapy‐resistant acute myeloid leukemia blasts and leukemia stem cells

• Published in: Cancer science 2021-08, Vol.112 (8), p.3233-3242
• Main Authors: Wu, Kangni, Wang, Li‐mengmeng, Liu, Meng, Xiu, Yanghui, Hu, Yongxian, Fu, Shan, Huang, He, Xu, Bing, Xiao, Haowen
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Animals; Antigens, Differentiation, T-Lymphocyte - metabolism; Antimitotic agents; Antineoplastic agents; Aprotinin; Bone marrow; Cancer; CD226; Chemotherapy; Cytolysis; Cytotoxicity; Cytotoxicity, Immunologic; Disease; Drug dosages; Drug Resistance, Neoplasm; Effector cells; Ethylenediaminetetraacetic acid; Experiments; Extracellular signal-regulated kinase; extracellular signal–regulatory kinase1/2; Female; Flow cytometry; Granule cells; HL-60 Cells; Humans; Immunotherapy; Immunotherapy, Adoptive; K562 Cells; Leukemia; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - therapy; Lymphocytes; Lymphocytes T; Lysosomal Membrane Proteins - metabolism; lysosome‐associated membrane protein 1; MAP Kinase Signaling System; Medical prognosis; Membrane proteins; Mice; Myeloid leukemia; Nectin; Original; Phosphorylation; Remission (Medicine); Stem cells; T cell receptors; T cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - transplantation; Treatment Outcome; Vγ9Vδ2 T cell; Xenograft Model Antitumor Assays
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15014

Vγ9Vδ2 T cells are attractive effector cells for immunotherapy with potent cytotoxic activity against a variety of malignant cells. However, the effect of Vγ9Vδ2 T cells on chemotherapy‐resistant acute myeloid leukemia (AML) blasts, especially highly refractory leukemia stem cells (LSCs) is still unknown. In this study, we investigated the effect of cytotoxicity of allogeneic Vγ9Vδ2 T cells on chemotherapy‐resistant AML cell lines, as well as on primary AML blasts and LSCs obtained from refractory AML patients. The results indicated that Vγ9Vδ2 T cells can efficiently kill drug‐resistant AML cell lines in vitro and in vivo, and the sensitivity of AML cells to Vγ9Vδ2 T cell–mediated cytotoxicity is not influenced by the sensitivity of AML cells to chemotherapy. We further found that Vγ9Vδ2 T cells exhibited a comparable effect of cytotoxicity against LSCs to primary AML blasts. More importantly, we revealed that the CD226–extracellular signal–regulatory kinase1/2 (ERK1/2)–lysosome‐associated membrane protein 1 (LAMP1) pathway is an important mechanism for Vγ9Vδ2 T cell–induced cytotoxicity against AML cells. First, Vγ9Vδ2 T cells recognized AML cells by receptor‐ligand interaction of CD226–Nectin‐2, which then induced ERK1/2 phosphorylation in Vγ9Vδ2 T cells. Finally, triggering the movement of lytic granules toward AML cells induced cytolysis of AML cells. The expression level of Nectin‐2 may be used as a novel marker to predict the susceptibility/resistance of AML cells to Vγ9Vδ2 T cell treatment. In this study, we indicated that Vγ9Vδ2 T cells can efficiently kill drug‐resistant acute myeloid leukemia (AML) cell lines in vitro and in vivo. We further found that Vγ9Vδ2 T cells exhibited a comparable effect of cytotoxicity against leukemia stem cells (LSCs) to primary AML blasts. More importantly, we revealed that Vγ9Vδ2 T cells induced cytotoxicity against AML cells via the CD226–extracellular signal–regulatory kinase1/2 (ERK1/2)–lysosome‐associated membrane protein 1 (LAMP1) pathway.