Abstract
BackgroundCD86 has great potential to be a new target of immunotherapy by regulating cancer immune response. However, it remains unclear whether CD86 is a friend or foe in lower-grade glioma (LGG).MethodsThe prognostic value of CD86 expression in pan-cancer was analyzed using Cox regression and Kaplan-Meier analysis with data from the cancer genome atlas (TCGA). Cancer types where CD86 showed prognostic value in overall survival and disease-specific survival were identified for further analyses. The Chinese Glioma Genome Atlas (CGGA) dataset were utilized for external validation. Quantitative real-time PCR (qRT-PCR), Western blot (WB), and Immunohistochemistry (IHC) were conducted for further validation using surgical samples from Jiangsu Province hospital. The correlations between CD86 expression and tumor immunity were analyzed using the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, Tumor IMmune Estimation Resource (TIMER) database, and expressions of immune checkpoint molecules. Gene Set Enrichment Analysis (GSEA) was performed using clusterprofiler r package to reveal potential pathways.ResultsPan-cancer survival analysis established CD86 expression as an unfavorable prognostic factor in tumor progression and survival for LGG. CD86 expression between Grade-II and Grade-III LGG was validated using qRT-PCR and WB. Additionally, CD86 expression in LGG with unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter was significantly higher than those with methylated MGMT (P<0.05), while in LGG with codeletion of 1p/19q it was significantly downregulated as opposed to those with non-codeletion (P<2.2*10-16). IHC staining validated that CD86 expression was correlated with MGMT status and X1p/19q subtypes, which was independent of tumor grade. Multivariate regression validated that CD86 expression acts as an unfavorable prognostic factor independent of clinicopathological factors in overall survival of LGG patients. Analysis of tumor immunity and GSEA revealed pivotal role of CD86 in immune response for LGG.ConclusionsIntegrated analysis shows that CD86 is an unfavorable prognostic biomarker in LGG patients. Targeting CD86 may become a novel approach for immunotherapy of LGG.
Highlights
Cancer cells escape surveillance of human immune system partly by activating immune checkpoint pathways, which leads to suppressed anti-cancer immune responses of the host [1, 2]
In Cox regression analysis, the results revealed that CD86 expression was significantly associated with survival rates in five cancer types, i.e., cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), lower-grade glioma (LGG), skin cutaneous melanoma (SKCM), thymoma (THYM) and uveal melanoma (UVM) (Figure 2)
The results on disease-specific survival (DSS) were in line with the overall survival (OS) analysis, showing similar effect of CD86 expression in the five cancer types: CESC (HR = 0.611, 95%confidence intervals (CI) [0.436, 0.856], Cox P = 0.004), LGG (HR = 1.555, 95%CI [1.261, 1.917], Cox P < 0.001), SKCM (HR = 0.696, 95%CI [0.604, 0.803], Cox P < 0.001), THYM (HR = 3.603, 95% CI [1.082, 11.993], Cox P = 0.037) and UVM (HR = 2.112, 95%CI [1.160, 3.845], Cox P = 0.014) (Figure 2B)
Summary
Cancer cells escape surveillance of human immune system partly by activating immune checkpoint pathways, which leads to suppressed anti-cancer immune responses of the host [1, 2]. CD86 promotes T-cell proliferation, function and survival by interacting with CD28 as a co-stimulator, while in activated T cells it interacts with CTLA-4 and acts as a suppressor [10, 11] In this bidirectional way, the interplay of CD86 with CD28 and CTLA‐4 are of great importance for immune responses against autoimmunity [12] and cancers [13]. Due to the fact that CD86 may serve as a key regulator in cancer immune response via T-cell-mediated mechanisms, it has great potential to be a new target of immunotherapy. It remains unclear whether CD86 is a friend or foe in pan-cancer given its dual-edge role in regulating immune response. It remains unclear whether CD86 is a friend or foe in lower-grade glioma (LGG)
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