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

Abstract

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 co-immunoprecipitation 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 co-stimulatory 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.

Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors

“…While studies in mice suggested a modest role for CD2 ( 29 , 58 ), it is clearly important in human T cell function ( 32 , 59 ), including elimination of cancerous ( 60 , 61 ) and virus-infected ( 62 ) cells. Defects in CD58 (either loss of expression or mutations) have been reported in B cell and T cell lymphomas ( 63 – 65 ), and CD2 expression on tumor-infiltrating T cells has been shown to correlate with their function in several cancers ( 66 ).…”

Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes

“…Disruption of the CD58-CD2 axis can lead to immune evasion not only through lack of T-cell costimulation through CD2, but also through increased inhibition of T cells through PD-L1/PD 1 signaling. 53 CD58 mutations lead to decreased CD58 mRNA expression and are associated with poor response to CAR T-cell therapy, but could represent a genetic marker for CD2 costimulation approaches. 54 As CD58 is coregulated by PD-L1, it will be of major interest to investigate whether incorporation of checkpoint inhibition to the frontline treatment can overcome the various genetic immune escape mechanisms present in PMBCL.…”

Proceedings from the Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA)

“…Finally, a research laboratory's experience performing multimodal high-resolution, single-cell and single nucleus sequencing coupled with spatial transcriptomics and whole-genome sequencing on trace amounts of archived tumor tissues (Anderson et al, 2022;Biermann et al, 2022), including melanoma (Wang et al, 2023), was discussed.…”