Single-cell transcriptomic and spatial analysis reveal the immunosuppressive microenvironment in relapsed/refractory...

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma characterized by a complex tumor microenvironment (TME).
• The progression and TME complexity in relapsed/refractory AITL (RR-AITL) remain poorly understood.

Purpose of the Study:

• To compare the cellular composition and spatial architecture of the TME between newly diagnosed AITL (ND-AITL) and RR-AITL.
• To identify key molecular and cellular mechanisms driving AITL progression and immune evasion.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC) were employed.
• Comparative analysis of cellular populations, transcriptional profiles, and spatial interactions in ND-AITL and RR-AITL samples.

Main Results:

• Malignant T follicular helper (Tfh) cells exhibit increased proliferation via YY1 activation in RR-AITL, correlating with poor prognosis.
• CD8+ T cell cytotoxicity is reduced in RR-AITL due to elevated inhibitory checkpoints (PD-1, TIGIT, CTLA4).
• B cells in RR-AITL show intermediate malignant transformation, expressing CD47 and PD-L1 for immune evasion.
• Myeloid cells in RR-AITL display impaired phagocytic activity and antigen presentation.
• Specific inhibitory ligand-receptor interactions (e.g., CLEC2D-KLRB1, CTLA4-CD86, MIF-CD74) are identified in RR-AITL.

Conclusions:

• RR-AITL is characterized by a distinct immunosuppressive TME with increased malignant Tfh cell activity and impaired cytotoxic T cells and myeloid cell function.
• B-cell transformation and specific ligand-receptor interactions contribute to immune evasion in RR-AITL.
• The study identifies potential therapeutic targets for RR-AITL, including targeting YY1 activation and inhibitory checkpoints.