Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Multiple myeloma (MM) patients treated with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells often experience relapse due to CAR T-cell suppression.
• CD200, an immune checkpoint overexpressed on aberrant plasma cells (aPCs) in MM, negatively impacts patient survival.
• Current preclinical models lack CD200 expression on multiple myeloma cell lines, limiting research into CD200-mediated suppression.

Purpose of the Study:

• To engineer multiple myeloma cell lines to express CD200, mimicking aPCs in MM.
• To investigate the suppressive effects of CD200 on BCMA- or TnMUC1-specific CAR T cells.
• To evaluate strategies for overcoming CD200-mediated suppression, including CD200 receptor knockout (CD200RKO), dominant-negative (CD200RDN), and CD28-switch variants.

Main Methods:

• Engineered MM cell lines to express CD200.
• Co-cultured engineered MM cells with clinical-stage CAR T cells targeting BCMA or TnMUC1.
• Assessed CAR T-cell function, including polyfunctionality, cytotoxicity, proliferation, metabolism, and performance in chronic antigen exposure assays.
• Utilized CRISPR-Cas9 for CD200RKO and CD200RDN modifications.
• Validated findings in murine xenograft models of MM.

Main Results:

• Engineered CD200-expressing MM cells suppressed CAR T-cell activity.
• The CD200 receptor-CD28 switch significantly enhanced CAR T-cell polyfunctionality, cytotoxicity, proliferation, metabolism, and performance.
• CD200RDN offered modest benefits, while CD200RKO impaired CAR T-cell metabolism and activity.
• These effects were confirmed in in vivo murine models.

Conclusions:

• CD200-mediated immune suppression is a critical factor in CAR T-cell therapy for multiple myeloma.
• Leveraging CD200 expression on aberrant plasma cells via a CD200R-CD28 switch presents a promising strategy to enhance CAR T-cell efficacy in MM.
• This approach could overcome immune suppression and improve therapeutic outcomes for multiple myeloma patients.