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.; Poźniak, Joanna; Shah, Shivem B.; Walsh, Zachary H; 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.; Vasan, Neil; Bakhoum, Samuel F.; Reiner, Steven L.; Bernatchez, Chantale; Sykes, Megan; Mace, Emily M.; Wucherpfennig, Kai W.; Schadendorf, Dirk; Bechter, Oliver; Shah, Parin; Schwartz, Gary K.; Marine, Jean–Christophe; Izar, Benjamin

doi:10.1016/j.ccell.2023.05.014

Cited by 18 publications

(7 citation statements)

References 65 publications

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“…In the accompanying study by Ho et al, 46 similar conclusions were drawn based on experiments conducted in different cell line and tumor models, with additional elaboration on the influence of CD58 expression on PD-L1 and vice versa, involving competing binding to CMTM6. On the other hand, our study provided further insights into the functional consequences of CMTM6-mediated regulation of PD-L1 and CD58.…”

Section: Discussionmentioning

confidence: 70%

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1

Miao,

Hu,

Mezzadra

et al. 2023

Cancer Cell

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Section: Discussionmentioning

confidence: 70%

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1

Miao,

Hu,

Mezzadra

et al. 2023

Cancer Cell

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“…Loss of CD58 eliminates Blinatumomab-induced T-cell activation [ 45 ]. CD58 − CD2 axis deficiency promotes immune escape of melanoma cells by reducing T-cell activation, tumor-infiltrating T-cell proliferation, and impairing PD-L1 protein stability [ 46 ]. The presence of Marvel transmembrane domain-containing 6 ( CMTM6 ), a positive regulator and molecular partner of PD-L1 , positively regulates CD58 expression as well.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of immune-related antigen CD58 in gliomas and analysis of its potential core related gene clusters

Tian,

Jia,

Wang

et al. 2024

Heliyon

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“…CD58 mutation or downregulated expression is common in melanoma and hematological tumors, and downregulation of CD58 is associated with immune evasion in melanoma and that disruption of CD58 in tumor cells confers functional impairment of CAR T cells [ 46 – 48 ]. Previous study has shown that CMTM6 is critical for CD58 stability and upregulation of PDL1 upon CD58 loss in melanoma [ 49 ]. Here we show a different mechanism in gastric cancer: CD58 is negatively posttranscriptionally regulated by HSPA4/ALKBH5 via m 6 A demethylation.…”

Section: Discussionmentioning

confidence: 99%

HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer

Suo,

Gao,

Chen

et al. 2024

J Exp Clin Cancer Res

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Introduction Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Recently, targeted therapies including PD1 (programmed cell death 1) antibodies have been used in advanced GC patients. However, identifying new biomarker for immunotherapy is still urgently needed. The objective of this study is to unveil the immune evasion mechanism of GC cells and identify new biomarkers for immune checkpoint blockade therapy in patients with GC. Methods Coimmunoprecipitation and meRIP were performed to investigate the mechanism of immune evasion of GC cells. Cocuture system was established to evaluate the cytotoxicity of cocultured CD8+ T cells. The clinical significance of HSPA4 upregulation was analyzed by multiplex fluorescent immunohistochemistry staining in GC tumor tissues. Results Histone acetylation causes HSPA4 upregulation in GC tumor tissues. HSPA4 upregulation increases the protein stability of m6A demethylase ALKBH5. ALKBH5 decreases CD58 in GC cells through m6A methylation regulation. The cytotoxicity of CD8+ T cells are impaired and PD1/PDL1 axis is activated when CD8+ T cells are cocultured with HSPA4 overexpressed GC cells. HSPA4 upregulation is associated with worse 5-year overall survival of GC patients receiving only surgery. It is an independent prognosis factor for worse survival of GC patients. In GC patients receiving the combined chemotherapy with anti-PD1 immunotherapy, HSPA4 upregulation is observed in responders compared with non-responders. Conclusion HSPA4 upregulation causes the decrease of CD58 in GC cells via HSPA4/ALKBH5/CD58 axis, followed by PD1/PDL1 activation and impairment of CD8+ T cell’s cytotoxicity, finally induces immune evasion of GC cells. HSPA4 upregulation is associated with worse overall survival of GC patients with only surgery. Meanwhile, HSPA4 upregulation predicts for better response in GC patients receiving the combined immunotherapy.

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

Cited by 18 publications

References 65 publications

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1

Clinical significance of immune-related antigen CD58 in gliomas and analysis of its potential core related gene clusters

HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer

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