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A novel prognostic biomarker LCP2 correlates with metastatic melanoma-infiltrating CD8⁺ T cells.

ABSTRACT: Lymphocyte cytosolic protein 2 (LCP2) is one of the SLP-76 family of adapters, which are critical intermediates in signal cascades downstream of several receptors. LCP2 regulates immunoreceptor signaling (such as T-cell receptors) and is also required for integrin signaling in neutrophils and platelets. However, the role of LCP2 in the tumor microenvironment is still unknown. In this study, we found a significant increase of mRNA and protein expression of LCP2 in metastatic skin cutaneous melanoma compared to normal skin. The upregulation of LCP2 was associated with good overall survival of patients with metastatic skin cutaneous melanoma, who received pharmacotherapy and radiation. GSEA signaling pathways analysis showed that LCP2 was involved in multiple pathways of immune response and correlation analysis revealed LCP2 was positively correlated with molecules in TCR signaling and 11 immune checkpoints, while LCP2 negatively correlated with 2 immune checkpoints in the metastatic skin cutaneous melanoma. According to the different expressions of LCP2, high LCP2 expression was positively correlated with more tumor-infiltrating CD8⁺ T cells. Furthermore, Kaplan-Meier plot indicated that LCP2 acted as a prognostic biomarker for progression-free survival of patients with metastatic skin cutaneous melanoma receiving anti-PD1 immunotherapy. In conclusion, our results integrated both the expression and function of LCP2 in melanoma using multiple tools, shedding light on the potential role of LCP2 in melanoma, and suggesting LCP2 serves as a prognostic biomarker and therapeutic target in anti-tumor immunity.

SUBMITTER: Wang Z

PROVIDER: S-EPMC8080722 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.

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A novel prognostic biomarker LCP2 correlates with metastatic melanoma-infiltrating CD8⁺ T cells.

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A novel prognostic biomarker LCP2 correlates with metastatic melanoma-infiltrating CD8+ T cells.

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A novel prognostic biomarker LCP2 correlates with metastatic melanoma-infiltrating CD8⁺ T cells.