Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer

Gupta, Prachi; Kadamberi, Ishaque P.; Mittal, Sonam; Tsaih, Shirng‐Wern; George, Jasmine; Kumar, Sudhir; Vijayan, Dileep K.; Geethadevi, Anjali; Parashar, Deepak; Topchyan, Paytsar; McAlarnen, Lindsey A.; Volkman, Brian F.; Cui, Weiguo; Zhang, Kam Y. J.; Vizio, Dolores Di; Chaluvally‐Raghavan, Pradeep; Pradeep, Sunila

doi:10.1002/advs.202104452

Cited by 31 publications

(39 citation statements)

References 35 publications

(35 reference statements)

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“…Among these pathways, those involving MAPK/ERK1/2 and AKT/GSK3β have been associated with HCC proliferation (13), while SPHK1 signaling has been associated with the epithelial-to-mesenchymal transition in HCC (37). SPHK1 induces T cell failure and upregulates the PD-1 ligand, creating an immunosuppressive TME (38,39). Similarly, activation of Wnt/β-catenin, MDM2/ p53, and YAP1 signaling leads to immunosuppression, and blocking such signaling can improve the efficacy of ICIs (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

Luo¹,

Liao²,

Liu³

et al. 2022

Pathol. Oncol. Res.

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Background: Hepatocellular carcinoma is the most common type of primary liver cancer, and it is associated with poor prognosis. It often fails to respond to immunotherapy, highlighting the need to identify genes that are associated with the tumor microenvironment and may be good therapeutic targets. We and others have shown that the Holliday cross-recognition protein HJURP can promote the proliferation, migration, and invasion by hepatocellular carcinoma cells, and that HJURP overexpression is associated with poor survival. Here we explored the potential relationship between HJURP and the tumor microenvironment in hepatocellular carcinoma.Methods: We used the Immuno-Oncology-Biological-Research (IOBR) software package to analyze the potential roles of HJURP in the tumor microenvironment. Using single-cell RNA sequencing data, we identified the cell clusters expressing abundant HJURP, then linked some of these clusters to certain bioprocesses using Gene Set Enrichment Analysis (GSEA). We validated the differential expression of HJURP in tumor-infiltrating CD8+ T cells, sorted by flow cytometry into populations based on the expression level of PD-1. We used weighted gene co-expression network analysis (WGCNA) to identify immunity-related genes whose expression strongly correlated with that of HJURP. The function of these genes was validated based on enrichment in Gene Ontology (GO) terms, and they were used to establish a prognosis prediction model.Results: IOBR analysis suggested that HJURP is significantly related to the immunosuppressive tumor microenvironment and was significantly related to T cells, dendritic cells, and B cells. Based on single-cell RNA sequencing, HJURP was strongly expressed in T cells, erythrocytes, and B cells from normal liver tissues, as well as in CD8+ T cells, dendritic cells, and one cluster of hepatocytes in hepatocellular carcinoma tissues. Malignant hepatocytes strongly expressing HJURP were associated with the downregulation of immune bioprocesses. HJURP expression was significantly higher in CD8+ T cells strongly expressing PD-1 than in those expressing no or intermediate levels of PD1. WGCNA identified two module eigengenes (comprising 397 and 84 genes) related to the tumor microenvironment. We identified 24 hub genes and confirmed that they were related to immune regulation. A prognostic risk score model based on expression of HJURP, PPT1, PML, and CLEC7A showed moderate ability to predict survival.Conclusion:HJURP is associated with tumor-infiltrating immune cells, immune checkpoints, and immune suppression in hepatocellular carcinoma. HJURP-related genes involved in immune responses may be useful for predicting patient prognosis.

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Section: Discussionmentioning

confidence: 99%

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

Luo¹,

Liao²,

Liu³

et al. 2022

Pathol. Oncol. Res.

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“…However, certain cell line-based studies showed that ectopic expression of E2F1 could sensitize tumor cells to chemotherapy (etoposide) or radiotherapy in LNCaP or PC3 cells ( 40 , 41 ). Interestingly, a recent study demonstrated that E2F1-mediated transcription is essential for sphingosine-1-phosphate (S1P)-induced upregulation of PD-L1 expression ( 42 ), which may partly explain why FRGPI-high patients responded better to anti-PD-L1 than FRGPI-low patients in our study. Cell division cycle 20 (CDC20) acts as an anaphase-promoting complex activator that controls the proper segregation of chromosomes in mitosis ( 43 ).…”

Section: Discussionmentioning

confidence: 68%

A novel ferroptosis-related gene prognostic index for prognosis and response to immunotherapy in patients with prostate cancer

et al. 2022

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BackgroundProstate cancer (PCa) is among the leading causes of cancer death worldwide. Ferroptosis refers to an iron-dependent form of regulated cell death and is involved in prostate tumorigenesis. A few ferroptosis-related gene signatures have been developed to predict the prognosis for PCa patients. However, previous signatures were typically established based on biochemical recurrence-free survival, which has proven not to be a good surrogate for overall survival (OS). This study aimed to construct a novel ferroptosis-related gene prognostic index (FRGPI) to predict disease-free survival (DFS) and response to immunotherapy for PCa patients after radical prostatectomy.MethodsGene expression and clinicopathological data on PCa patients were obtained from the TCGA database. Ferroptosis-related hub genes associated with DFS of PCa patients were identified by an in-depth bioinformatics analysis using a novel and comprehensive algorithm based on functional enrichment, consensus clustering, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network construction. The FRGPI was established on the basis of the genes selected using multivariate cox regression analysis and further validated in two additional PCa cohorts. Next, the clinicopathological, molecular, and immune profiles were characterized and compared between FRGPI-high and FRGPI-low subgroups. Finally, the predictive role of the FRGPI in response to immunotherapy was estimated using a metastatic urothelial cancer cohort treated with an anti-PD-L1 agent.ResultsThe FRGPI was constructed based on four genes (E2F1, CDC20, TYMS, and NUP85), and FRGPI-high patients had worse DFS than FRGPI-low patients. Multivariate cox regression analysis revealed that FRGPI could act as an independent prognostic factor for PCa patients after radical prostatectomy. A prognostic nomogram comprising the FRGPI and other clinicopathological parameters was established to predict the DFS for PCa patients quantitatively. In addition, comprehensive results demonstrated that high FRGPI scores showed a significantly positive correlation with worse clinicopathological features, higher mutation counts, increased frequency of copy number variations (CNVs), higher homologous recombination deficiency (HRD) and immune scores, higher mRNAsi, and more importantly, enhanced sensitivity to immunotherapy.ConclusionsFRGPI is not only a promising and robust prognostic biomarker, but also a potential indicator of immunotherapeutic outcomes for PCa patients after radical prostatectomy.

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“…In addition, exosomes are nanovesicles that facilitate communication between cells. Exosomes are important in the development and progression of cancer [ 203 ]. Exosomes include functional components such as proteins, lipids, mRNA molecules, and ncRNAs which act as carriers of extracellular information [ 204 ].…”

Section: Therapeutic Approaches For Targeting Ncrnas In CCmentioning

confidence: 99%

Emerging Roles and Potential Applications of Non-Coding RNAs in Cervical Cancer

Parashar

Singh

Gupta

et al. 2022

Genes

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Cervical cancer (CC) is a preventable disease using proven interventions, specifically prophylactic vaccination, pervasive disease screening, and treatment, but it is still the most frequently diagnosed cancer in women worldwide. Patients with advanced or metastatic CC have a very dismal prognosis and current therapeutic options are very limited. Therefore, understanding the mechanism of metastasis and discovering new therapeutic targets are crucial. New sequencing tools have given a full visualization of the human transcriptome’s composition. Non-coding RNAs (NcRNAs) perform various functions in transcriptional, translational, and post-translational processes through their interactions with proteins, RNA, and even DNA. It has been suggested that ncRNAs act as key regulators of a variety of biological processes, with their expression being tightly controlled under physiological settings. In recent years, and notably in the past decade, significant effort has been made to examine the role of ncRNAs in a variety of human diseases, including cancer. Therefore, shedding light on the functions of ncRNA will aid in our better understanding of CC. In this review, we summarize the emerging roles of ncRNAs in progression, metastasis, therapeutics, chemo-resistance, human papillomavirus (HPV) regulation, metabolic reprogramming, diagnosis, and as a prognostic biomarker of CC. We also discussed the role of ncRNA in the tumor microenvironment and tumor immunology, including cancer stem cells (CSCs) in CC. We also address contemporary technologies such as antisense oligonucleotides, CRISPR–Cas9, and exosomes, as well as their potential applications in targeting ncRNAs to manage CC.

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Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer

Cited by 31 publications

References 35 publications

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

A novel ferroptosis-related gene prognostic index for prognosis and response to immunotherapy in patients with prostate cancer

Emerging Roles and Potential Applications of Non-Coding RNAs in Cervical Cancer

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