Multiple Myeloma Cells Resistant to T-cell Therapies Exhibit a CD45+ Immunoevasive Phenotype

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Multiple myeloma (MM) remains largely incurable despite novel treatments.
• BCMA-targeted therapies, including CAR T cells and TCEs, show promise but face resistance.
• Understanding resistance mechanisms is crucial for improving MM treatment outcomes.

Purpose of the Study:

• To investigate the mechanisms of resistance in multiple myeloma cells following BCMA-targeted therapies.
• To identify cellular changes and molecular pathways associated with treatment persistence.

Main Methods:

• Ex vivo analysis of bone marrow samples treated with BCMA CAR T cells, TCEs, or activated T cells.
• Flow cytometry to assess CD45 expression.
• Validation in patient samples and an in vivo mouse model.
• Bulk RNA-sequencing and mechanistic studies.

Main Results:

• Persisting MM cells consistently showed CD45 upregulation, forming focal surface patches.
• Mechanistic studies implicated secreted HSP70.
• RNA-sequencing revealed increased expression of LAG-3, IFN-γ signaling, and PD-L1.

Conclusions:

• T cell-redirecting therapy (TCRT) induces an immuno-evasive phenotype in MM cells characterized by CD45 upregulation.
• This phenotype involves immune checkpoint activation (LAG-3, PD-L1).
• Combination strategies involving TCRT and checkpoint inhibitors may overcome resistance in relapsed/refractory MM.