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. Issue 8 (4th July 2021)

• Record Type: Journal Article
• Authors: Wu, Kangni; Wang, Li‐mengmeng; Liu, Meng; Xiu, Yanghui; Hu, Yongxian; Fu, Shan; Huang, He; Xu, Bing; Xiao, Haowen
• Is Part Of: Cancer science. Volume 112:Issue 8(2021)
• Page Start: 3233
• Page End: 3242
• Publication Date: 2021-07-04
• Subjects: acute myeloid leukemia -- CD226 -- extracellular signal–regulatory kinase1/2 -- lysosome‐associated membrane protein 1 -- Vγ9Vδ2 T cell; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15014
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: 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. Abstract : 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.