&lt;p&gt;Resistance Mechanism of PD-1/PD-L1 Blockade in the Cancer-Immunity Cycle&lt;/p&gt;

Zhuang, Yuan; Liu, Chang; Liu, Jiaqing; Li, Guang

doi:10.2147/ott.s239398

Cited by 38 publications

(22 citation statements)

References 98 publications

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“…A large number of basic and clinical experiments are currently underway, including allogeneic stem cell transplantation, antitumor vaccines, proinflammatory cytokines, chimeric antigen receptors, and adoptive T cell metastasis. One of the most promising methods considered is ICT (Yu et al, 2018;Zhu et al, 2019;Zhuang et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Finds Immune Gene Markers Related to the Prognosis of Bladder Cancer

et al. 2020

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Bladder cancer is one of the most common malignant tumors of the urinary system that seriously threatens the health of a population. In recent years, the application of immunotherapy has significantly changed the treatment of bladder cancer, but only some patients can benefit from the treatment with immune-checkpoint inhibitors. Many problems are unsolved in the field of bladder cancer immunotherapy, especially in the search for genes that are critical to the level of immune cell infiltration and new effective therapeutic targets. We attempted to use bioinformatics analysis to identify immune gene markers related to the prognosis of bladder cancer and to establish a prognostic signature for bladder cancer patients based on their immune gene expression profiles. We used univariate Cox proportional hazards regression analysis, the least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox proportional hazards regression analysis from The Cancer Genome Atlas bladder cancer cohort (TCGA-BLCA). Fifteen genes related to prognosis were screened using the survival analysis, correlation analysis, cancer and adjacent cancer differential expression analysis, and mutation analysis. The potential biological role of these genes was determined using survival analysis and principal component analysis (PCA). The receiver operating characteristic (ROC) curve assesses the prognostic value of the predictive signature. The gene ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), Gene set enrichment analysis (GSEA), and other methods were used to reveal the differential gene enrichment in the signaling pathways and cellular processes of high-and low-risk groups. The single-sample GSEA (ssGSEA) method was used to quantify the infiltration levels of 24 immune cells in the tumor immune microenvironment and these immune genes were found to be closely related to the tumor immune microenvironment. In summary, we screened 15 immune genes that were closely related to bladder cancer overall survival (OS) and may be potential prognostic indicators of bladder cancer. They may have research and clinical application value in bladder cancer immunotherapy. We used 15 immune genes to construct a new immune-related gene signature that was verified and could be helpful in improving individualized prognosis of patients with bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Finds Immune Gene Markers Related to the Prognosis of Bladder Cancer

et al. 2020

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“…[2][3][4] However, considerable challenges, such as lack of durable remission, low response rate, drug resistance and immunerelated adverse effects, still remain to be addressed. [5][6][7][8][9][10] It is generally considered that PD-L1 expressed on the tumor cell surface is upregulated in the tumor microenvironment to activate PD-1 on CD8 T cells, delivering the co-inhibitory signals and thereby suppressing T cell function. 11 However, except being presented on the tumor cell surface, PD-L1 is also dynamically circulating inside tumor cells 12 13 as well as excreted into extracellular space via the exosomes, 14 15 contributing to the resistance to anti-PD-L1 antibodies.…”

Section: Introductionmentioning

confidence: 99%

THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy

Chi²,

Deng

et al. 2021

J Immunother Cancer

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BackgroundThe abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood.MethodsCombined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA.ResultsTHADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer.ConclusionsOur data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.

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“…In many cases, their number, distribution, phenotype, and function can change as the tumor progresses. Studies have shown that the number of DCs in peripheral blood of patients with head and neck squamous carcinoma is different from that of healthy individuals [ 159 ]. In a model of spontaneous ovarian cancer, Scarlett and colleagues observed a functional switch in DCs from an immunostimulatory to an immunosuppressive phenotype.…”

Section: Dendritic Cells and Cross-presentation In Cancermentioning

confidence: 99%

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

Mpakali

Stratikos

2021

Cancers

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Recent clinical successes of cancer immunotherapy using immune checkpoint inhibitors (ICIs) are rapidly changing the landscape of cancer treatment. Regardless of initial impressive clinical results though, the therapeutic benefit of ICIs appears to be limited to a subset of patients and tumor types. Recent analyses have revealed that the potency of ICI therapies depends on the efficient presentation of tumor-specific antigens by cancer cells and professional antigen presenting cells. Here, we review current knowledge on the role of antigen presentation in cancer. We focus on intracellular antigen processing and presentation by Major Histocompatibility class I (MHCI) molecules and how it can affect cancer immune evasion. Finally, we discuss the pharmacological tractability of manipulating intracellular antigen processing as a complementary approach to enhance tumor immunogenicity and the effectiveness of ICI immunotherapy.

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<p>Resistance Mechanism of PD-1/PD-L1 Blockade in the Cancer-Immunity Cycle</p>

Cited by 38 publications

References 98 publications

Bioinformatics Analysis Finds Immune Gene Markers Related to the Prognosis of Bladder Cancer

Bioinformatics Analysis Finds Immune Gene Markers Related to the Prognosis of Bladder Cancer

THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

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