Work

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

Year: 2025

Type: article

Abstract: 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 pilot trial.

Source: Cell Reports Medicine

DOI: 10.1016/j.xcrm.2025.102036