The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.

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.

• Authors: Patricia Ho, Johannes C Melms, Meri Rogava, Chris J Frangieh, Joanna Poźniak, Shivem B Shah, Zachary Walsh, Oleksandr Kyrysyuk, Amit Dipak Amin, Lindsay Caprio, Benjamin T Fullerton, Rajesh Kumar Soni, Casey R Ager, Jana Biermann, Yiping Wang, Mohsen Khosravi-Maharlooei, Giorgia Zanetti, Michael Mu, Hijab Fatima, Emily K Moore, Neil Vasan, Samuel F Bakhoum, Steven L Reiner, Chantale Bernatchez, Megan Sykes, Emily M Mace, Kai W Wucherpfennig, Dirk Schadendorf, Oliver Bechter, Parin Shah, Gary K Schwartz, Jean-Christophe Marine, Benjamin Izar
• Journal: Cancer cell (Cancer Cell) Vol. 41 Issue 7 Pg. 1207-1221.e12 (07 10 2023) ISSN: 1878-3686 [Electronic] United States
• PMID: 37327789 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen
• CD58 Antigens

Topics

• Mice
• Animals
• B7-H1 Antigen (genetics)
• T-Lymphocytes
• CD58 Antigens (chemistry, metabolism)
• Melanoma (genetics, metabolism)
• Lymphocyte Activation