KLRG1 re-defines a leukemic clone of CD8 effector T cells sensitive to PI3K inhibitor in T cell large granular lymphocytic leukemia

作者：Lele Zhang, Chen Qiu, Ruonan Li, Yucan Shen, Lin Tian, Hong Chang, Qian Liang, Hong Pan, Zhen Gao, Weiwang Li, Jingyu Zhao, Liwei Fang, Xiao Yu, Jing Xu, Zhexiang Kuang, Weiping Yuan, Yajing Chu, Jun Shi · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.102036 · 被引用次数：4 · 研究领域：Chronic Lymphocytic Leukemia Research、Lymphoma Diagnosis and Treatment、Immune Cell Function and Interaction

T cell large granular lymphocytic leukemia (T-LGLL) is a clonal lymphoproliferative disorder, originated from mature effector memory CD8 + T cells. It is a challenge to define the leukemic T cell clones due to the lack of definite markers. Here, we decipher the heterogeneity of CD8 + T cells using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and T cell receptor (TCR) profiling in T-LGLL patients. A CD8 + terminal effector subset is identified, marked by reduced KLRG1 expression. Remarkably, high fidelity of leukemic clonality was specially limited in KLRG1 − large granular lymphocytes (LGLs), not seen in KLRG1 + LGLs in T-LGLL patients or in KLRG1 − LGLs in healthy controls. KLRG1 − leukemic LGLs show upregulated PI3K signaling with enhanced cytotoxicity and exhaustion, persisting after conventional treatment. In a pilot trial of linperlisib (a PI3Kδ inhibitor) for refractory cases, 7 of 8 participants quickly respond with satisfactory safety. This study is registered at ClinicalTrials.gov ( NCT05676710 ). • A distinct CD8 + TE3 cluster with reduced KLRG1 expression is identified in T-LGLL • PI3K-Akt signaling pathway is upregulated in KLRG1 − leukemic LGLs • PI3K inhibitor is a safe and effective regimen for refractory T-LGLL Zhang et al. report that reduced KLRG1 expression is a potential marker for identifying leukemic large granular lymphocytes and show that PI3K inhibitor could be a promising therapeutic approach for refractory T-LGLL in a pi...