Sorting nexin 6 interacts with Cullin3 and regulates programmed death ligand 1 expression.
TL;DR: In this paper, the authors demonstrate that sorting nexin 6 (SNX6) is a novel regulator of PD-L1 expression, and that SNX6 decreases the interaction between the adaptor protein speckle-type POZ protein and Cullin3.
About: This article is published in FEBS Letters.The article was published on 2021-10-01. It has received 3 citations till now. The article focuses on the topics: Sorting nexin 6 & Ubiquitin ligase.
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TL;DR: In this article , the role and molecular mechanisms of E3 ligases-mediated regulation of PD-1 and PD-L1 in tumor microenvironment are discussed, and how E3-dependent regulation alters anti-PD-1/PD-L 1 efficacy.
Abstract: The tumor microenvironment (TME) is the tumor surrounding environment, which is critical for tumor development and progression. TME is also involved in clinical intervention and treatment outcomes. Modulation of TME is useful for improving therapy strategies. PD-L1 protein on tumor cells interacts with PD-1 protein on T cells, contributing to T cell dysfunction and exhaustion, blockage of the immune response. Evidence has demonstrated that the expression of PD-1/PD-L1 is associated with clinical response to anti-PD-1/PD-L1 therapy in cancer patients. It is important to discuss the regulatory machinery how PD-1/PD-L1 protein is finely regulated in tumor cells. In recent years, studies have demonstrated that PD-1/PD-L1 expression was governed by various E3 ubiquitin ligases in TME, contributing to resistance of anti-PD-1/PD-L1 therapy in human cancers. In this review, we will discuss the role and molecular mechanisms of E3 ligases-mediated regulation of PD-1 and PD-L1 in TME. Moreover, we will describe how E3 ligases-involved PD-1/PD-L1 regulation alters anti-PD-1/PD-L1 efficacy. Altogether, targeting E3 ubiquitin ligases to control the PD-1/PD-L1 protein levels could be a potential strategy to potentiate immunotherapeutic effects in cancer patients.
8 citations
TL;DR: CUL3/SPOP formed a complex to promote PD-L1 degradation to inhibit ovarian cancer cell immune escape and increase chemosensitivity, offering a therapeutic target for ovarian cancer treatment.
Abstract: Background Cancer immune escape is a main obstacle in designing effective anticancer therapeutic approaches. Our work was aimed to explore the function of cullin 3 (CUL3) in ovarian cancer cell immune escape and chemosensitivity. Method Gain and loss of function assays were conducted to investigate the interactions among CUL3, speckle type POZ protein (SPOP) and programmed death ligand-1 (PD-L1) as well as their effects on ovarian cell malignant phenotypes and chemosensitivity. A mouse model of xenografted ovarian cells was further established for in vivo substantiation. Result Poorly-expressed CUL3 and SPOP were found in ovarian cancer. Overexpression of CUL3 reduced malignant features as well as immune escape of ovarian cancer cells but enhanced chemosensitivity. Functionally, CUL3 degraded PD-L1 protein by forming complex with SPOP. Overexpression of CUL3 inhibited tumor formation and enhanced chemosensitivity of ovarian cancer cells in mice by degrading PD-L1 protein. Conclusion All in all, CUL3/SPOP formed a complex to promote PD-L1 degradation to inhibit ovarian cancer cell immune escape and increase chemosensitivity, offering a therapeutic target for ovarian cancer treatment.
1 citations
TL;DR: In this article , the authors explored the correlation between SNX29 expression and 33 types of malignancies via TCGA and GTEx and found associations between the SNX-29 gene and tumor mutation burden, micro-satellite instability, immunoinhibition-related genes and autophagy related genes.
Abstract: Abstract Background There is growing evidence that the SNX family is critical for clinical prognosis, immune infiltration and drug sensitivity in many types of tumors. The relationships between the SNX29 gene and clinical prognosis as well as pan-cancer cell infiltration and drug sensitivity have not been fully elucidated. Methods In the current study, we explored the correlation between SNX29 expression and 33 types of malignancies via TCGA and GTEx. The relationship between SNX29 expression and prognostic outcome in the pan-caner cohort was also analyzed. Immune infiltration, microsatellite instability, tumor mutational burden and potential therapeutic targets of SNX29 were investigated by analyzing public databases. Results The expression of SNX29 was found to be significantly upregulated in most tumor tissues compared to normal tissues. SNX29 expression was associated with prognosis and clinical stage. In the immune infiltration analysis, a significant relationship was found between SNX29 expression and the level of immune infiltration. In addition, we found associations between the SNX29 gene and tumor mutation burden, microsatellite instability, immunoinhibition-related genes and autophagy-related genes. Finally, the expression of SNX29 was significantly associated with the sensitivity of various tumor cell lines to 8 antitumor drugs. These results suggest that SNX29 expression is important in determining the progression, immune infiltration and drug sensitivity of various cancers. Conclusion This study provides novel insights into the potential pan-cancer targets of SNX29.
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TL;DR: It is reported here that the ligand of PD-1 (PD-L1), an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells, is a member of the B7 gene family.
Abstract: PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
4,633 citations
TL;DR: Induction of the B7-H1/PD-1 pathway may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity and may explain how melanomas escape immune destruction despite endogenous antitUMor immune responses.
Abstract: In the movie The Great Escape , “problem” prisoners with multiple escape attempts are put in an “escape-proof” POW camp, where they use their cleverness and specialized skills to outwit their captors. However, when it comes to escaping, even Steve McQueen doesn’t have anything on cancer cells. Although human cancers express tumor antigens recognized by the immune system, host immune responses often fail to control tumor growth. Taube et al. now explain one way in which tumor cells may adapt to escape from immune surveillance.
The researchers found a strong association between expression of the immune-inhibitory molecule B7-H1 (PD-L1) on melanocytes and immune cell infiltration into tumors in patients with different stages of melanoma. The B7-H1+ melanocytes were found directly adjacent to the immune cells, with interferon-γ detected at the melanocyte–immune cell interface. Interferon-γ, which is secreted by the immune cells, induces B7-H1 expression; thus, the tumor may adapt by causing immune cells to trigger their own inhibition. Indeed, patients with B7-H1+ metastatic melanoma had prolonged overall survival when compared with B7-H1− metastatic melanoma patients, perhaps suggesting that B7-H1 expression by the tumors is stimulated by a more successful immune response. It remains to be seen whether blocking B7-H1 in these patients will further improve survival. But it is clear that for both prisoners and tumors, adaptation is the key to escape.
1,924 citations
TL;DR: The current state of understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, is reviewed, and conceptual gaps in knowledge are highlighted.
Abstract: Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge. Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069–86. ©2018 AACR.
1,893 citations
TL;DR: The roles of these B7 molecules in the dynamic interactions between tumours and the host immune system, including their expression, regulation and function in the tumour microenvironment are focused on.
Abstract: The B7 family consists of activating and inhibitory co-stimulatory molecules that positively and negatively regulate immune responses. Recent studies have shown that human and rodent cancer cells, and stromal cells and immune cells in the cancer microenvironment upregulate expression of inhibitory B7 molecules and that these contribute to tumour immune evasion. In this Review, we focus on the roles of these B7 molecules in the dynamic interactions between tumours and the host immune system, including their expression, regulation and function in the tumour microenvironment. We also discuss novel therapeutic strategies that target these inhibitory B7 molecules and their signalling pathways to treat human cancer.
1,411 citations
TL;DR: The roles of the PD-1-PD-L1 axis in cancer is reviewed, focusing on recent findings on the mechanisms that regulate PD-L 1 expression at the transcriptional, posttranscriptional, and protein level, to inform the design of more precise and effective cancer immune checkpoint therapies.
1,211 citations