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Antigen glycosylation regulates efficacy of CAR T cells targeting CD19
Amanda Heard1, Jack H Landmann1, Ava R Hansen2
1Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
Abstract:
While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy.
Insights
Signal peptide peptidase-like 3 (SPPL3) in B cells regulates resistance to chimeric antigen receptor (CAR) T cell therapy. SPPL3 affects CD19 protein levels and glycosylation, impacting CAR T cell function and anti-tumor activity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T cell therapy shows promise for B cell malignancies but often lacks durable remission.
- Mechanisms of CAR T cell failure are critical for improving treatment efficacy.
- CD19 gene disruption is a known resistance mechanism, but other tumor-intrinsic factors remain underexplored.
Purpose of the Study:
- To identify novel tumor-intrinsic mechanisms driving resistance to CD19-targeted CAR T cell therapy.
- To investigate the role of Signal peptide peptidase-like 3 (SPPL3) in regulating CAR T cell efficacy.
Main Methods:
- Utilized a pre-clinical model of B cell malignancies.
- Assessed the impact of SPPL3 expression levels on CD19 protein and its post-translational modifications.
- Evaluated the functional consequences for CAR T cell effector function and anti-tumor cytotoxicity.
Main Results:
- SPPL3 expression in malignant B cells was identified as a key regulator of resistance to CAR T cell therapy.
- Loss of SPPL3 led to hyperglycosylation of CD19, impairing CAR T cell function.
- Overexpression of SPPL3 resulted in CD19 protein loss, also conferring resistance.
Conclusions:
- Post-translational modification of CD19, influenced by SPPL3, represents a significant mechanism of antigen escape from CAR T cell therapy.
- Targeting SPPL3 or its downstream effects may overcome resistance and enhance CAR T cell therapy outcomes.
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