Identification of clonally expanded γδ T-cell populations during CAR-T cell therapy

Area of Science:

• Immunology
• Cell Biology
• Oncology

Background:

• Anti-CD19 Chimeric Antigen Receptor (CAR)-T cell therapy is a promising treatment for B cell malignancies.
• Clinical success of CAR-T therapy depends on both the therapeutic product and the patient's immune system.
• The specific role and behavior of gamma delta T (γδ T) cells in CAR-T cell therapy are not well understood.

Purpose of the Study:

• To investigate the transcriptional heterogeneity, clonal expansion, and dynamics of γδ T cells in patients undergoing anti-CD19 CAR-T cell therapy.
• To elucidate the contribution of γδ T cells to the immune response during CAR-T cell therapy.
• To identify potential targets or strategies for enhancing CAR-T cell therapy efficacy by understanding γδ T cell behavior.

Main Methods:

• Longitudinal single-cell multi-omics analysis of γδ T cells from four patients receiving anti-CD19 CAR-T cell therapy.
• Utilized single-cell RNA sequencing (scRNA-seq), antibody-derived tag sequencing (AbSeq), and full-length TCRγδ sequencing.
• Analyzed gene expression profiles, protein expression, and T cell receptor sequences to assess clonal expansion and differentiation.

Main Results:

• Identified clonally expanded γδ T cell populations with significant transcriptional heterogeneity, forming seven distinct clusters.
• Observed plasticity in T cell differentiation and temporal dynamics of large γδ T cell clones, suggesting ongoing expansion.
• Detected cluster-specific homing tendencies based on chemokine marker analysis and found unexpectedly high frequencies of Vδ1 and Vδ3 cells with unique expression profiles.

Conclusions:

• γδ T cells exhibit dynamic and heterogeneous behavior following anti-CD19 CAR-T cell therapy.
• The distinct transcriptional and protein expression profiles of expanded γδ T cell subsets, including Vδ1 and Vδ3, offer new insights.
• Understanding these γδ T cell dynamics can contribute valuable information for optimizing CAR-T cell therapies in B cell malignancies.