The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity Journal Article
| Authors: | Ho, P.; Melms, J. C.; Rogava, M.; Frangieh, C. J.; Poźniak, J.; Shah, S. B.; Walsh, Z.; Kyrysyuk, O.; Amin, A. D.; Caprio, L.; Fullerton, B. T.; Soni, R. K.; Ager, C. R.; Biermann, J.; Wang, Y.; Khosravi-Maharlooei, M.; Zanetti, G.; Mu, M.; Fatima, H.; Moore, E. K.; Vasan, N.; Bakhoum, S. F.; Reiner, S. L.; Bernatchez, C.; Sykes, M.; Mace, E. M.; Wucherpfennig, K. W.; Schadendorf, D.; Bechter, O.; Shah, P.; Schwartz, G. K.; Marine, J. C.; Izar, B. |
| Article Title: | 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. © 2023 Elsevier Inc. |
| Keywords: | genetics; t lymphocyte; t-lymphocytes; mouse; animal; metabolism; animals; mice; cancer immunotherapy; melanoma; lymphocyte activation; chemistry; lymphocyte function associated antigen 3; programmed death 1 ligand 1; cancer immunology; immune checkpoint blockade; cd2; pdl1; b7-h1 antigen; single-cell rna-sequencing; balance of co-inhibitory/co-stimulator; cancer immune evasion; cd58; crispr-cas9 screen; mass spec screen; resistance to immune checkpoint blockade; cd58 antigens |
| Journal Title: | Cancer Cell |
| Volume: | 41 |
| Issue: | 7 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2023-07-10 |
| Start Page: | 1207 |
| End Page: | 1221.e12 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2023.05.014 |
| PUBMED: | 37327789 |
| PROVIDER: | scopus |
| PMCID: | PMC10524902 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
