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Published on: May 6, 2019
The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity
Patricia Ho1, Johannes C Melms1, Meri Rogava1
1Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA.
Abstract:
The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.
Insights
Cancer cells balance immune signals using CD58 and PD-L1. Intact CD58 promotes anti-tumor immunity and predicts treatment response, while defects lead to immune evasion.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Cell Biology
Background:
- Cancer immune evasion relies on balancing immune-inhibitory and -stimulatory signals.
- The CD58-CD2 axis plays a role in anti-tumor immunity and treatment response.
Purpose of the Study:
- To investigate the role of cancer cell-intrinsic CD58 expression in anti-tumor immunity.
- To identify molecular mechanisms regulating CD58 stability and its interplay with PD-L1.
Main Methods:
- Patient-derived co-cultures
- Humanized mouse models
- Single-cell RNA-sequencing
- CRISPR-Cas9 screens
- Proteomics
Main Results:
- Intact cancer cell CD58 expression and CD2 ligation are crucial for anti-tumor immunity and predict treatment response.
- Defects in the CD58-CD2 axis impair T cell activation, infiltration, and proliferation, while increasing PD-L1.
- CMTM6 is identified as a key regulator of CD58 stability and PD-L1 upregulation upon CD58 loss.
- Competition for CMTM6 binding influences CD58 and PD-L1 endosomal recycling versus degradation.
Conclusions:
- A critical axis involving CD58 and CD2 regulates cancer immunity and immune evasion.
- CMTM6 mediates the balance between immune stimulatory (CD58) and inhibitory (PD-L1) signals.
- Understanding this axis provides a molecular basis for cancer immune evasion and potential therapeutic strategies.
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