Calnexin Impairs the Antitumor Immunity of CD4+ and CD8+ T Cells

Chen, Yi‐Chen; Ma, Dawei; Wang, Xi; Fang, Juan; Liu, Xiangqi; Song, Jingjing; Li, Xinye; Ren, Xianyue; Li, Qiusheng; Li, Qunxing; Wen, Sheng; Luo, Liqun; Xia, Juan; Cui, Jun; Zeng, Gucheng; Chen, Lieping; Cheng, Bin; Wang, Zhi

doi:10.1158/2326-6066.cir-18-0124

Cited by 27 publications

(22 citation statements)

References 46 publications

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“…Calnexin, an essential endoplasmic reticulum (ER) chaperone protein, plays a vital role in the synthesis of HLA class I surface antigen complex. Calnexin was revealed to inhibit the proliferation and activation of CD4 + T and CD8 + T cells, and it may impair the function of T cells by upregulating the expression of PD-1 in oral squamous cancer (Chen et al, 2019). Consistent with our results, it was found that decreased expression of CANX was associated with favorable survival outcome (Patel et al, 2013) and served as a biomarkers for tumor response in glioblastoma (Demeure et al, 2016).…”

Section: Discussionsupporting

confidence: 86%

“…On the contrary, increased abundance of M1-type macrophages, and CD8 + T cells were associated with favorable survival outcomes. As mentioned above, the six risk genes can not only have intrinsic roles in tumor growth and apoptosis (i.e., Guo and Dixon, 2016;Chen et al, 2019;Jego et al, 2019), but also serve as the immune-regulatory factors via antigen-presenting cells (APCs) and effector T lymphocytes (Borrego et al, 2006;Surmann et al, 2015;Ling et al, 2017;Zhu et al, 2018;Chen et al, 2019;Wu et al, 2019). Hence, it is worthwhile to explore the relationship between the risk groups and infiltrative immune cells in primary LGG.…”

Section: Discussionmentioning

confidence: 99%

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Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

et al. 2020

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Objective: Despite several clinicopathological factors being integrated as prognostic biomarkers, the individual variants and risk stratification have not been fully elucidated in lower grade glioma (LGG). With the prevalence of gene expression profiling in LGG, and based on the critical role of the immune microenvironment, the aim of our study was to develop an immune-related signature for risk stratification and prognosis prediction in LGG. Methods: RNA-sequencing data from The Cancer Genome Atlas (TCGA), Genome Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) were used. Immune-related genes were obtained from the Immunology Database and Analysis Portal (ImmPort). Univariate, multivariate cox regression, and Lasso regression were employed to identify differentially expressed immune-related genes (DEGs) and establish the signature. A nomogram was constructed, and its performance was evaluated by Harrell's concordance index (C-index), receiver operating characteristic (ROC), and calibration curves. Relationships between the risk score and tumor-infiltrating immune cell abundances were evaluated using CIBERSORTx and TIMER. Results: Noted, 277 immune-related DEGs were identified. Consecutively, 6 immune genes (CANX, HSPA1B, KLRC2, PSMC6, RFXAP, and TAP1) were identified as risk signature and Kaplan-Meier curve, ROC curve, and risk plot verified its performance in TCGA and CGGA datasets. Univariate and multivariate Cox regression indicated that the risk group was an independent predictor in primary LGG. The prognostic signature showed fair accuracy for 3-and 5-year overall survival in both internal (TCGA) and external (CGGA) validation cohorts. However, predictive performance was poor in the recurrent LGG cohort. The CIBERSORTx algorithm revealed that naïve CD4 + T cells were significant higher in low-risk group. Conversely, the infiltration levels of

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

et al. 2020

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“…Flow cytometry. Staining cell surface or intracellular targets was described previously (18). Briefly, single-cell preparations were stained for dead cells using a Zombie NIR Fixable Viability Kit (Biolegend).…”

Section: In Vitro and In Vivo T-cell Proliferationmentioning

confidence: 99%

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Chen

Wang

et al. 2019

Clinical Cancer Research

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Purpose: Multiple negative regulators restrict the ability of T cells to attack tumors. This work demonstrates the role of PI3Kinteracting protein 1 (Pik3ip1) in restraining T-cell responses and antitumor immunity. Experimental Design: An anti-Pik3ip1 mAb was generated to identify the Pik3ip1 expression pattern of hematopoietic cells. Pik3ip1 À/À mice and a Pik3ip1 fusion protein were generated to investigate the effect of Pik3ip1 on T-cellmediated antitumor immunity in MC38 and B16-F10 tumor models. Immunoblotting and confocal microscopy were used to identify inhibitory effects of Pik3ip1 on T-cell receptor (TCR) signaling. Pik3ip1 expression was quantified, and its impact on T-cell function in human tumors was measured. Results: We demonstrated that Pik3ip1 was predominantly expressed on T cells and served as an essential rheostat for T-cell-mediated immunity. A Pik3ip1 genetic deficiency led to enhanced T-cell responsiveness upon immunization with a neoantigen. Pik3ip1 À/À mice exhibited a marked increase in antitumor immunity and were resistant to tumor growth. Furthermore, Pik3ip1 extracellular domain fusion protein enhanced MC38 tumor growth was observed. Mechanistically, we found that Pik3ip1 inhibited TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region. Consistent with the results from the mouse models, PIK3IP1 expression correlated with T-cell dysfunction in human tumors. Conclusions: Our data reveal a critical role for Pik3ip1 as a novel inhibitory immune regulator of T-cell responses and provide a potential molecular target for cancer immunotherapy.

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“…Together with calreticulin, calnexin serves as a molecular chaperone, which prevents the aggregation and export of incompletely folded proteins from the ER, a mechanism involved in the metastatic progression of tumors (248). As CALX can escape from the ER and be transported to the plasma membrane or released outside the cell, its impact on the human immune system was recently investigated by Chen et al, who reported that its upregulation was associated with the inhibition of T-cell infiltration in tumor tissues (249).…”

Section: Endoplasmic Reticulummentioning

confidence: 99%

Biomarkers of tumor invasiveness in proteomics (Review)

et al. 2020

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Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of references involving studies on the cancer metastatic process has doubled since 2010, while the last 5 years have seen the development of novel technologies combining deep proteome coverage capabilities with quantitative consistency and accuracy. To highlight key findings within this huge amount of information, the present review identified a list of tumor invasive biomarkers based on both the literature and data collected on a biocollection of experimental cell lines, tumor models of increasing invasiveness and tumor samples from patients with colorectal or breast cancer. Crossing these different data sources led to 76 proteins of interest out of 1,245 mentioned in the literature. Information on these proteins can potentially be translated into clinical prospects, since they represent potential targets for the development and evaluation of innovative therapies, alone or in combination. Herein, a systematical review of the biology of each of these proteins, including their specific subcellular/extracellular or multiple localizations is presented. Finally, as an important advantage of quantitative proteomics is the ability to provide data on all these molecules simultaneously in cell pellets, body fluids or paraffin-embedded sections of tumors/invaded tissues, the significance of some of their interconnections is discussed.

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Calnexin Impairs the Antitumor Immunity of CD4+ and CD8+ T Cells

Cited by 27 publications

References 46 publications

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Biomarkers of tumor invasiveness in proteomics (Review)

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