Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment...

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• T cell recognition is crucial for anti-tumor immunity.
• Understanding T cell diversity is key to optimizing immunotherapies like PD-1 blockade, especially in multiple myeloma (MM).

Purpose of the Study:

• To characterize T cell diversity in the bone marrow of healthy adults and patients with precursor and full-blown MM.
• To identify T cell phenotypes associated with dysfunction and explore potential therapeutic targets and prognostic markers in MM.

Main Methods:

• Single-cell RNA and T cell receptor sequencing were used to analyze bone marrow T cells from healthy individuals and MM patients.
• Flow cytometry was employed to assess the CD27-negative and CD27-positive T cell ratio.
• Dual targeting of PD-1+LAG3 or PD-1+TIGIT was tested in a mouse model of MM.

Main Results:

• Large T cell clones in MM patients exhibited multiple immune checkpoints, indicating potential dysfunction.
• Dual blockade of PD-1 with LAG3 or TIGIT partially restored T cell function in a mouse model.
• The ratio of CD27-negative to CD27-positive T cells served as a surrogate for clonal T cell expansion and was an independent prognostic factor in MM patients.

Conclusions:

• Characterizing T cell phenotypes and diversity is vital for understanding MM immunopathogenesis and treatment response.
• Combined targeting of immune checkpoints like PD-1, LAG3, and TIGIT shows promise for restoring T cell function in MM.
• The CD27 T cell ratio is a potential prognostic biomarker for MM patients, particularly those undergoing lenalidomide-based therapies.