RT Journal Article
SR Electronic
T1 The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.21.485049
DO 10.1101/2022.03.21.485049
A1 Patricia Ho
A1 Johannes C. Melms
A1 Meri Rogava
A1 Chris J. Frangieh
A1 Shivem B. Shah
A1 Zachary Walsh
A1 Oleksandr Kyrysyuk
A1 Amit Dipak Amin
A1 Lindsay Caprio
A1 Benjamin T. Fullerton
A1 Rajesh Soni
A1 Casey R. Ager
A1 Jana Biermann
A1 Yiping Wang
A1 Michael Mu
A1 Hijab Fatima
A1 Emily K. Moore
A1 Neil Vasan
A1 Samuel F. Bakhoum
A1 Steven L. Reiner
A1 Chantale Bernatchez
A1 Emily M. Mace
A1 Kai W. Wucherpfennig
A1 Dirk Schadendorf
A1 Gary K. Schwartz
A1 Benjamin Izar
YR 2022
UL http://biorxiv.org/content/early/2022/03/23/2022.03.21.485049.abstract
AB The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 coimmunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary costimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.Competing Interest StatementThe authors have declared no competing interest.