Affordable Access

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

  • Ho, Patricia;
  • Melms, Johannes C;
  • Rogava, Meri;
  • Frangieh, Chris J;
  • Pozniak, Joanna;
  • Shah, Shivem B;
  • Walsh, Zachary;
  • Kyrysyuk, Oleksandr;
  • Amin, Amit Dipak;
  • Caprio, Lindsay;
  • Fullerton, Benjamin T;
  • Soni, Rajesh Kumar;
  • Ager, Casey R;
  • Biermann, Jana;
  • Wang, Yiping;
  • Khosravi-Maharlooei, Mohsen;
  • Zanetti, Giorgia;
  • Mu, Michael;
  • Fatima, Hijab;
  • Moore, Emily K;
  • And 13 more
Publication Date
Jul 10, 2023
External links


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. / status: published

Report this publication


Seen <100 times