scholarly journals CD8+ T Cell-Based Molecular Classification With Heterogeneous Immunogenomic Landscapes and Clinical Significance of Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiangkun Wu ◽  
Dongmei Jiang ◽  
Hongling Liu ◽  
Xiaofan Lu ◽  
Daojun Lv ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Significance ◽  
Immune Escape ◽  
Tumor Biology ◽  
Molecular Classification ◽  
Molecular Clusters ◽  
Copy Number Loss ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels

The tumor microenvironment (TME) exerts a high impact on tumor biology and immunotherapy. The heterogeneous phenotypes and the clinical significance of CD8+ T cells in TME have not been fully elucidated. Here, a comprehensive immunogenomic analysis based on multi-omics data was performed to investigate the clinical significance and tumor heterogeneity between CD8+ T cell-related molecular clusters. We identified two distinct molecular clusters of ccRCC (C1 and C2) in TCGA and validated in E-MTAB-1980 cohorts. The C1 cluster was characterized by unfavorable prognosis, increased expression levels of CD8+ T cell exhaustion markers, high immune infiltration levels as well as more immune escape mechanisms. The C2 cluster was featured by favorable prognosis, elevated expression levels of CD8+ T cell effector markers, low load of copy number loss and low frequency of 9p21.3 deletion. Moreover, the effect of molecular classifications on Nivolumab therapeutic efficacy in the CheckMate 025 cohort was examined, and the C2 cluster exhibited a better prognosis. Taken together, we determine two CD8+ T cell-related molecular clusters in ccRCC, and provide new insights for evaluating the functions of CD8+ T cells. Our molecular classification is a potential strategy for prognostic prediction and immunotherapeutic guidance for ccRCC patients.

scholarly journals Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 956
Author(s):  
Kirsten Freitag ◽  
Sara Hamdan ◽  
Matthias J. Reddehase ◽  
Rafaela Holtappels
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Antigenic Drift ◽  
Murine Cytomegalovirus ◽  
High Avidity ◽  
Infected Cells ◽  
Cd8 T Cell Memory

CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.

scholarly journals Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

2008 ◽  
Vol 14 (12) ◽  
pp. 1390-1395 ◽  
Author(s):  
Angel Varela-Rohena ◽  
Peter E Molloy ◽  
Steven M Dunn ◽  
Yi Li ◽  
Megan M Suhoski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Hiv 1

IL-7R–dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3370-3381 ◽  
Author(s):  
Ingrid Saba ◽  
Christian Kosan ◽  
Lothar Vassen ◽  
Tarik Möröy
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Strong Reduction ◽  
Expression Levels ◽  
Cell Numbers ◽  
Finger Protein

Abstract T cells originate from early T lineage precursors that have entered the thymus and differentiate through well-defined steps. Mice deficient for the BTB/POZ domain of zinc finger protein-1 (Miz-1) almost entirely lack early T lineage precursors and have a CD4−CD8− to CD4+CD8+ block causing a strong reduction in thymic cellularity. Miz-1ΔPOZ pro-T cells cannot differentiate in vitro and are unable to relay signals from the interleukin-7R (IL-7R). Both STAT5 phosphorylation and Bcl-2 up-regulation are perturbed. The high expression levels of SOCS1 found in Miz-1ΔPOZ cells probably cause these alterations. Moreover, Miz-1 can bind to the SOCS1 promoter, suggesting that Miz-1 deficiency causes a deregulation of SOCS1. Transgenic overexpression of Bcl-2 or inhibition of SOCS1 restored pro-T cell numbers and their ability to differentiate, supporting the hypothesis that Miz-1 is required for the regulation of the IL-7/IL-7R/STAT5/Bcl-2 signaling pathway by monitoring the expression levels of SOCS1.

scholarly journals Serum-derived exosomes promote CD8+ T cells to overexpress PD-1, affecting the prognosis of hypopharyngeal carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qian Gao ◽  
Hui-Ting Liu ◽  
Yu-Qin Xu ◽  
Lin Zhang ◽  
Yuan-Ru Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Poor Prognosis ◽  
Cell Function ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Serum Exosomes

Abstract Background Hypopharyngeal cancer (HPC) is associated with a poor prognosis and a high recurrence rate. Immune escape is one of the reasons for the poor prognosis of malignant tumors. Programmed cell death ligand 1 (PD-L1) and programmed cell death-1 (PD-1) have been shown to play important roles in immune escape. However, the role of PD-1/PD-L1 in HPC remains unclear. In this experiment, we investigated the effect of exosomes from HPC patient serum on CD8+ T cell function and PD-1/PD-L1 expression and, thus, on prognosis. We hope to provide guidance for the identification of new targets for HPC immunotherapy. Methods PD-1 and CD8 expression in 71 HPC tissues and 16 paracarcinoma tissues was detected by immunohistochemistry. Concurrently, the clinicopathological data of the patients were obtained to conduct correlation analysis. Exosomes were isolated from serum and then identified by Western blotting (WB), transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). Flow cytometry was used to assess the activity of CD8+ T cells after exosome stimulation. The effects of exosomes on the ability of CD8+ T cells to kill FaDu cells were assessed by CCK-8 assay. The expression of IL-10 and TGF-β1 was measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in HPC tissue samples was evaluated by immunohistochemistry, and the relationship between PD-1/PD-L1 expression and prognosis was investigated with patient specimens. Results PD-1 expression was significantly upregulated on CD8+ T cells in tumor tissues compared with those in normal tissues. The overall survival (OS) and disease-free survival (DFS) of PD-1-overexpressing patients were decreased. Serum exosomes from patients can elevate PD-1 expression on CD8+ T cells and suppress their killing capacity and secretory function. The rate of positive PD-L1 expression was increased in HPC tissues compared with paracancerous tissues. The DFS and OS of the PD-1(+)-PD-L1(+) group were significantly lower than those of the PD-1(−)-PD-L1(−) group. Conclusion Our findings indicate that serum exosomes from HPC patients can inhibit CD8+ T cell function and that the PD-1-PD-L1 pathway plays an important role in the immune escape of HPC. Exosomes combined with immunotherapy may guide the treatment of patients with advanced disease in the future.

scholarly journals 677 Reverse abscopal effect: intertumoral heterogeneity suppresses systemic CD8 T cell-mediated antitumor immunity and confers PD-1 inhibitor resistance in synchronous melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A705-A705
Author(s):  
Shuyang Qin ◽  
Booyeon Han ◽  
Alexander Chacon ◽  
Alexa Melucci ◽  
Alyssa Williams ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Abscopal Effect ◽  
Immunogenic Tumor ◽  
Ifn Γ

BackgroundDespite recent advancements in systemic therapy, only a minority of metastatic patients develop meaningful clinical responses to immune checkpoint inhibitors. Inherent genetic instability of melanoma generates genomically and microenvironmentally distinct metastases. These different tumor microenvironments (TMEs) contain numerous T cell suppression mechanisms, such as upregulation of the PD-1/PD-L1 exhaustion pathway. However, as synchronous metastases share one host immune system, intertumoral heterogeneity may result in increasing cross-talk between metastases that impairs systemic antitumor immunity and promotes PD-1 immunotherapy resistance.MethodsYUMM 1.7 (less immunogenic) and YUMMER 1.7 (more immunogenic cell line derived from YUMM following UVB irradiation) melanoma cell lines were simultaneously injected into opposite flanks of the same mice as a model of synchronous melanoma. We assessed tumor growth in wildtype, interferon-gamma (IFN-γ) knockout, and CD8-depleted mice as well as in response to PD-1 inhibitor. We characterized the TME with flow cytometry and performed TCR sequencing on tumor-infiltrating CD8 T cells.ResultsDistinct TMEs were observed for YUMM and YUMMER tumors simultaneously grown in the same mouse. The presence of the less immunogenic YUMM tumor allows the more immunogenic YUMMER tumors to escape IFN-γ and CD8 T cell-mediated rejection, despite abundant tumor-infiltrating, clonally expanded CD8 T cells. Identical immunodominant CD8 T cell clones were found in both YUMM and YUMMER tumors within the same mouse. Synchronous YUMMER-infiltrating CD8 T cells exhibit suppressed phenotypes, including increased persistence of surface PD-1 and decreased surface CD107a expressions. Simultaneously, these synchronous YUMMER tumors additionally upregulate macrophage surface PD-L1 expression, which potentially contributes to tumor immune escape. Lastly, synchronous YUMMER tumors become resistant to PD-1 inhibition, in direct contrast to control YUMMER tumors.ConclusionsIn a host with multiple melanoma lesions, immunogenicity of all tumors contribute to the systemic antitumor immune response. We show that two synchronous tumors with synonymous mutations (<40%), as is the case with metastatic patients, lead to skewed CD8 T cell expansion of the same clones in both tumors. The presence of a less immunogenic tumor prevents CD8 and IFN-γ mediated rejection of the more immunogenic tumor. Furthermore, CD8 T cells in the more immunogenic tumor exhibit decreased effector function and increased resistance to PD-1 blockade, as tumor-infiltrating macrophages concurrently become more immunosuppressive. These results are highly suggestive of a “reverse abscopal effect,” by which immunologically “cold” tumors generate systemic immunosuppression that facilitate PD-1 immunotherapy resistance and immune escape of all other tumors in synchronous metastatic melanoma patients.AcknowledgementsWe would like to thank Dr. Marcus Bosenberg from the Department of Dermatology at Yale University for kindly gifting us with the YUMMER 1.7 murine melanoma cell line.Ethics ApprovalAnimal experiments were approved by the University Committee on Animal Resources and performed in accordance with University of Rochester approved guidelines.

scholarly journals Genomic Landscape of Chinese Clear Cell Renal Cell Carcinoma Patients With Venous Tumor Thrombus Identifies Chromosome 9 and 14 Deletions and Related Immunosuppressive Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Shaoxi Niu ◽  
Kan Liu ◽  
Yong Xu ◽  
Cheng Peng ◽  
Yao Yu ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Carcinoma ◽  
Primary Tumor ◽  
Clear Cell ◽  
Chromosome 9 ◽  
Genetic Profile ◽  
Copy Number Loss ◽  
Cell Renal Cell Carcinoma ◽  
Immunosuppressive Microenvironment ◽  
Matched Primary Tumor

BackgroundClear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with a poor clinical outcome. Although several studies have examined the genomic features of ccRCC, the genetic profile of VTT along with its matched primary tumor has not been fully elucidated.Materials and methodsSamples of VTT tissues and matched primary tumor tissues from ccRCC patients (n = 25), as well as primary tumor tissues from patients without VTT (n = 25) were collected and analyzed using whole-exome sequencing. Four additional ccRCC patients who were unfit for surgery were treated with an anti-programmed death receptor-1 (PD-1) monoclonal antibody (Toripalimab, 240 mg, Q3W, IV).ResultsBy comparing the primary kidney tumors from ccRCC patients with or without VTT, a relatively higher prevalence of BAP1 and KDM5C alterations were found in ccRCC patients with VTT, and these alterations were associated with worse overall survival in the kidney renal clear cell carcinoma (KIRC) database. Based on subclone analysis, VTT was predicted to primarily originate directly from the primary renal mass. A significantly higher prevalence of CELSR2 and TET2 alterations were identified in the VTTs compared with the matched primary tumors. An increased prevalence of DNA damage repair genes, especially those involved in homologous recombination repair and non-homologous end joining, was found in ccRCC patients with VTT. Notably, VTT was characterized by the increase incidence of copy number loss in the whole exome (p &lt; 0.05), particularly in the chromosome 9 and 14 regions. Deletion of chromosome 9 and 14 was associated with worse survival, unfavorable clinical features, and the presence of an immunosuppressive microenvironment, which was characterized by higher infiltration of regulatory T cells, follicular helper T cells, and resting mast cells, but lower counts of resting CD4 memory T cells and CD8 positive T cells. A significantly lower count of CD4+ and CD8+ tumor-infiltrated lymphocytes was identified in the VTT samples comparing with matched primary tumor. Of note, three out of the four ccRCC patients with VTT in our cohort who were treated with the anti-PD-1 therapy exhibited remarkable remission in the renal mass but no notable shrinkage in the VTT mass.ConclusionOur study revealed the genetic profile of Chinese ccRCC patients with VTT, and identified multiple features associated with known poor outcomes, including gene alterations and copy number loss. The deletions in chromosomes 9 and 14, and the associated immunosuppressive microenvironment may indicate limited sensitivity to anti-PD-1/PD-L1 monotherapy in VTT.

CAR T-Cells for Glioblastoma: Current Concepts, Challenges and Future Perspectives

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012193
Author(s):  
P. Karschnia ◽  
N. Teske ◽  
N. Thon ◽  
M. Subklewe ◽  
JC. Tonn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Immune Escape ◽  
Basic Structure ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Glioblastoma is the most common malignant primary brain tumor and associated with a poor prognosis even after multimodal therapy. Chimeric antigen receptor (CAR) T-cells have emerged as a promising therapeutic avenue in glioblastoma. CARs incorporate antigen-recognition moieties that endow autologous T-cells with specificity against antigens expressed on glioblastoma (e.g. IL-13Rα2, EGFRvIII, and HER2). Compelling anti-tumor effects of such therapy have been shown in murine glioblastoma models. In humans, five phase I/II studies on IL-13Rα2-, EGFRvIII-, and HER2-directed CAR T-cells for the treatment of glioblastoma patients have been published suggesting an acceptable safety profile. However, anti-tumor effects fell short of expectations in these initial clinical studies. Tumor heterogeneity, antigen loss, and the immunosuppressive tumor microenvironment are among the most important factors to limit the efficacy of CAR T-cell therapy in glioblastoma. Novel target antigens, modification of CAR T-cell design, the combination of CAR T-cell therapy with other therapeutic approaches, but also the use of CAR NK-cells or CAR macrophages may optimize anti-tumor effects. Numerous clinical trials studying such approaches are ongoing, as well as several preclinical studies. With an increasing understanding of immune-escape mechanisms of glioblastoma and novel manufacturing techniques for CARs, CAR T-cells may provide clinically relevant activity in glioblastoma. This review focuses on the use of CAR T-cells in glioblastoma, but also introduces the basic structure, mechanisms of action, and relevant side effects of CAR T-cells.

scholarly journals Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 696 ◽  
Author(s):  
Bianca Simon ◽  
Dennis C. Harrer ◽  
Beatrice Schuler-Thurner ◽  
Gerold Schuler ◽  
Ugur Uslu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Dna And Rna ◽  
Antigen Loss ◽  
Antigen Presenting

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.

Inhibitory Effects of Lactic Acid on Human Antigen-Specific CD8+ T-Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3844-3844
Author(s):  
Marina Kreutz ◽  
Karin Fischer ◽  
Petra Hoffmann ◽  
Simon Volkl ◽  
Matthias Edinger ◽  
...  
Keyword(s):  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Cd8 T Cells ◽  
Acid Production ◽  
Cell Function ◽  
Immune Escape ◽  
Lactic Acid Production ◽  
Target Cells ◽  
Thymidine Uptake

Abstract A characteristic feature of inflammatory lesions or tumor sites is local acidosis, which is attributed to the local increase in lactic acid production. We studied the effect of such an acidic environment on the immune functions of antigen-specific CD8+ T-cells by incubating the cells in the presence of various concentrations of lactic acid for up to 48h. CD8+ T-cells were isolated from healthy donors and expanded by weekly stimulation with autologous dendritic cells pulsed with a mutated HLA-A2-binding Melan-A (ELAGIGILTV) peptide. The obtained T cell population consisted of at least 90% CD8+ and about 60% Melan-A specific T cells, as determined by Melan-A multimer staining. Incubation of CD8+ T cells with up to 20mM lactic acid for 24h did not cause T-cell apoptosis or cell death as determined by combined annexin/propidium iodide staining. However, the proliferative capacity of CD8+ T cells, as determined by 3H-thymidine uptake, was strongly inhibited. Similar results were obtained when we determined cytokine production and cytotoxic activity of the cells after a 24h culture period in 5-20 mM lactic acid. Production of both, IL-2 and IFN-gamma was strongly diminished in comparison to untreated cells, as determined by intracellular staining after stimulation with PMA/ionomycin for 5h in the presence of monensin. Analysis of the antigen-specific cytolytic capacity revealed that CD8+ T cells pre-cultured with lactic acid were less effective in killing antigen-loaded T2 target cells as compared to untreated CD8+ T cells. In parallel, the intracellular contents of the cytotoxic effector molecules granzyme-B and perforin was diminished. Re-adjusting the pH of the medium to a physiological value of pH7.4 could partially revert the effect of lactic acid. Treatment of CD8+ T cells with sodium lactate instead of lactic acid had no inhibitory effect. We conclude, that lactic acid is an important modulator of CD8+ T-cell function and may contribute, together with other factors, to immune escape mechanisms in the tumor environment.

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