scholarly journals The Identification of a Tumor Infiltration CD8+ T-Cell Gene Signature That Can Potentially Improve the Prognosis and Prediction of Immunization Responses in Papillary Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jie Wang ◽  
Meiying Huang ◽  
Peng Huang ◽  
Jingjie Zhao ◽  
Junhua Tan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Papillary Renal Cell Carcinoma ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
Risk Scores ◽  
Tumor Infiltration

BackgroundCD8+ T cells, vital effectors pertaining to adaptive immunity, display close relationships to the immunization responses to kill tumor cells. Understanding the effect exerted by tumor infiltration CD8+ T cells in papillary renal cell carcinoma (papRCC) is critical for assessing the prognosis process and responses to immunization therapy in cases with this disease.Materials and ApproachesThe single-cell transcriptome data of papRCC were used for screening CD8+ T-cell-correlated differentially expressed genes to achieve the following investigations. On that basis, a prognosis gene signature associated with tumor infiltration CD8+ T cell was built and verified with The Cancer Genome Atlas data set. Risk scores were determined for papRCC cases and categorized as high- or low-risk groups. The prognosis significance for risk scores was assessed with multiple-variate Cox investigation and Kaplan–Meier survival curves. In addition, the possible capability exhibited by the genetic profiles of cases to assess the response to immunization therapy was further explored.ResultsSix hundred twenty-one cell death-inhibiting RNA genes were screened using single-cell RNA sequencing. A gene signature consisting of seven genes (LYAR, YBX1, PNRC1, TCF25, MYL12B, MINOS1, and LINC01420) was then identified, and this collective was considered to be an independent prognosis indicator that could strongly assess overall survival in papRCC. In addition, the data allowed papRCC cases to fall to cohorts at high and low risks, exhibiting a wide range of clinically related features as well as different CD8+ T-cell immunization infiltration and immunization therapy responses.ConclusionsOur work provides a possible explanation for the limited response of current immunization checkpoint-inhibiting elements for combating papRCC. Furthermore, the researchers built a novel genetic signature that was able to assess the prognosis and immunotherapeutic response of cases. This may also be considered as a promising therapeutic target for the disease.

A mouse model for cancer immunoediting with renal cell carcinoma to explore mechanisms of immune escape.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11074-11074
Author(s):  
Elizabeth Bigger ◽  
Michael Quigley ◽  
Yiping Yang
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Cancer Immunoediting ◽  
Cancer Immunosurveillance

11074 Background: Cancer immunosurveillance is the immune system's ability to recognize and destroy newly arising malignant cells. Recent data suggests that the immune system functions also to apply a selective pressure, leading to growth of less immunogenic tumors, a process termed cancer immunoediting. However, direct experimental evidence to support this hypothesis has been lacking. Methods: We examined the interaction between tumor and tumor-specific CD8 T cells in vivo with a model tumor antigen, influenza hemagglutinin (HA), in a renal cell carcinoma cell line (Renca-HA) and studied the HA-specific CD8 T cell response to Renca-HA in vivo. Naïve HA-specific CD8 T cells (Thy1.1+) purified from HA-TCR transgenic mice that recognize a Kd-restricted HA epitope were transferred into congenic Thy1.2+recipients inoculated the day prior with Renca-HA or wild type Renca (Renca-WT). At subsequent time points, recipient lymphocytes and pulmonary tumors were harvested and analyzed. Results: Four days after transfer, vigorous proliferation of HA-specific CD8 T cells was detected in Renca-HA inoculated mice, but not Renca-WT inoculated mice, leading to activation and effector differentiation of HA-specific T cells. HA-specific CD8 T cell activation resulted in destruction of Renca-HA in vivo, causing a significant (p <0.001) reduction of tumor burden and prolongation of survival. However, a small fraction of Renca-HA tumor cells survived immune-mediated killing and evaded immune surveillance. Microarray technology identified upregulation of transforming growth factor β-3 (TGF-β3) expression in edited Renca-HA, but not in unedited Renca-HA, compared with Renca-WT, confirmed by real-time quantitative PCR. Functional abrogation of TGF-β3 signaling on tumor-specific CD8 T cells delayed Renca HA tumor growth in vivo. Conclusions: These data provide direct evidence for the cancer immunosurveillance and immunoediting processes, and suggest that tumor induction of TGFβ-3 during the immunoediting process suppresses tumor-specific CD8 T cell function in vivo, allowing tumor immune escape. Our results provide mechanistic insights as well as potential strategies to block cancer immune evasion.

scholarly journals A Tumor-Infiltration CD8+ T Cell-Based Gene Signature for Facilitating the Prognosis and Estimation of Immunization Responses in HPV+ Head and Neck Squamous Cell Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yingning Wu ◽  
Lingzhang Meng ◽  
Kai Cai ◽  
Jingjie Zhao ◽  
Siyuan He ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Head And Neck ◽  
Single Cell ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
Low Risk ◽  
Risk Scores

BackgroundCD8+ T cells, which play a vital role in response to adaptive immunity, are closely related to the immunization responses to kill tumor cells. Understanding the effects exerted by tumor-infiltrated CD8+ T cells in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) patients is critical for predicting their prognosis as well as their responses towards immunization-related therapy.Materials and MethodsHNSCC single cell transcriptome was used to screen for differentially expressed genes (DEGs) based on CD8+ T cells. A gene signature associated with CD8+ T cells was built and verified with the cancer genome atlas dataset with a view to predicting the prognosis of HNSCC patients. Risk scores were calculated for HNSCC cases and categorized into either high- or low-risk cohorts. The prognosis-correlated data of the risk scores were analyzed by using Kaplan-Meier survival curves and multi-variate Cox regression plots. In addition, the possibility of using the genetic profiles to predict responses toward immunization-related therapy was explored.ResultsFrom the DEGs screened from the sequencing of single-cell RNA, a gene signature of 4 genes (ACAP1, ANKRD28, C12orf75, and M6PR) were identified. It was seen that these genes could predict overall survival in HPV+ HNSCC patients. In addition, high- and low-risk HPV+ HNSCC patients showed marked differences in their CD8+ T-cell infiltration due to immunization when clinical characteristics were taken into consideration. This correlated with their immunization therapy responses.ConclusionsOur work provides insights into explaining the restricted responses of current immunization checkpoint inhibiting substances in HPV+ HNSCC patients. A novel genetic signature to predict the prognosis and immunization-correlated therapeutic responses is presented. This will provide potential new therapeutic opportunities for HPV+ HNSCC patients.

scholarly journals DNA-Demethylating Agents enhance cytolytic activity of CD8+ T Cells and anti-tumor immunity

2017 ◽  
Author(s):  
Helen Loo Yau ◽  
Ankur Chakravarthy ◽  
Felipe Campos de Almeida ◽  
David Allard ◽  
Rajat Singhania ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cytolytic Activity ◽  
Cell Tumor ◽  
Type I ◽  
Tumor Infiltration ◽  
Activation Markers ◽  
Viral Mimicry

AbstractRecent studies have shown that DNA methyltransferase inhibitors (DNMTi) can induce IRF7 activation and Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. By performing a large pan-cancer analysis using TCGA data, we determined that IRF7 activation is associated with higher CD8+ T cell tumor infiltration and higher cytolytic activity across multiple cancer types. Accordingly, we demonstrate that DNMTi treatment results in increased CD8+ T cell tumor infiltration, enhanced cytolytic activity and CD8+ T cell dependent tumor growth inhibition. Finally, we show that DNMTi triggers a process marked by the induction of viral mimicry directly on CD8+ T cells, leading to activation of dsRNA sensing pathway, and up-regulation of T cell activation markers, effector cytokines, and Granzyme B. Taken together, our findings suggest that dsRNA sensing pathway activation in the immune compartment, through pharmacological DNA demethylation, is a viable strategy for boosting anti-tumor immune response.

Association of preoperative neutrophil-to-lymphocyte ratio with immune populations in the tumor microenvironment of patients with clear cell renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 688-688
Author(s):  
Alejandro Sanchez ◽  
Ming Liu ◽  
Briana Nixon ◽  
Mazyar Ghanaat ◽  
Renzo DiNatale ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Populations ◽  
Cell Renal Cell Carcinoma ◽  
Sarcomatoid Differentiation

688 Background: Currently, there are no blood biomarkers that reflect the composition of immune cells in the tumor microenvironment (TME) of patients with clear cell renal cell carcinoma (ccRCC). High pre-operative neutrophil-to-lymphocyte ratio (NLR) is associated with adverse oncologic outcomes in ccRCC. However, how NLR relates to the immune cell composition in the TME is not well understood. Methods: We performed flow cytometry on tumor and adjacent normal renal tissue from a prospective cohort of patients who underwent surgery from 6/2015-7/2017. Immune cell populations, as a percent of total CD45+, were compared to baseline age, sex, body mass index (BMI), SSIGN score, sarcomatoid differentiation, and AJCC stage (I-IV). NLR was calculated using pre-operative absolute neutrophil-to-lymphocyte counts and further categorized as inflamed if NLR was ≥ 3. Correlations between continuous variables were performed using Spearman’s rank correlation. Comparisons of means were made using the Wilcoxon signed-rank test. Results: Among 48 patients, 32 (71%) were male, median age was 59 (IQR 52-66), BMI of 38.5 (IQR 26-32.6), SSIGN score of 8 (IQR 5-12), 9 (20%) had sarcomatoid differentiation, and 20 (44%) had metastases at presentation. No correlations were found between age, BMI, and different immune cell populations or NLR. A higher ratio of tissue resident (CD8a+CD49a+CD103+) to circulating (CD8a+CD49a-CD103-) CD8+ T-cells in the TME was associated with increasing stage at presentation (p = 0.02). Inflamed patients had similar total CD45+, CD8+ T cell, CD4+ T cell, and macrophage immune infiltration. However, inflamed patients had a higher proportion of CD8+ Tres infiltration (p = 0.04) and a trend towards higher neutrophil infiltration (p = 0.15). Conclusions: A higher proportion of resident CD8+T-cells correlated with advanced disease at presentation. NLR may reflect a change in the type of CD8+T cell population found in the TME. This population of CD8+ T-cells, and NLR as a possible biomarker should be validated and further investigated in a larger cohort of patients. Funding: Ruth L. Kirschstein Research Service Award T32CA082088 (A.S., M.G.)

scholarly journals Construction of a Promising Tumor-Infiltrating CD8+ T Cells Gene Signature to Improve Prediction of the Prognosis and Immune Response of Uveal Melanoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifang Sun ◽  
Jian Wu ◽  
Yonggang Yuan ◽  
Yumin Lu ◽  
Ming Luo ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
Low Risk ◽  
Immune Related Genes

BackgroundCD8+ T cells work as a key effector of adaptive immunity and are closely associated with immune response for killing tumor cells. It is crucial to understand the role of tumor-infiltrating CD8+ T cells in uveal melanoma (UM) to predict the prognosis and response to immunotherapy.Materials and MethodsSingle-cell transcriptomes of UM with immune-related genes were combined to screen the CD8+ T-cell-associated immune-related genes (CDIRGs) for subsequent analysis. Next, a prognostic gene signature referred to tumor-infiltrating CD8+ T cells was constructed and validated in several UM bulk RNA sequencing datasets. The risk score of UM patients was calculated and classified into high- or low-risk subgroup. The prognostic value of risk score was estimated by using multivariate Cox analysis and Kaplan–Meier survival analysis. Moreover, the potential ability of gene signature for predicting immunotherapy response was further explored.ResultsIn total, 202 CDIRGs were screened out from the single-cell RNA sequencing of GSE139829. Next, a gene signature containing three CDIRGs (IFNGR1, ANXA6, and TANK) was identified, which was considered as an independent prognostic indicator to robustly predict overall survival (OS) and metastasis-free survival (MFS) of UM. In addition, the UM patients were classified into high- and low-risk subgroups with different clinical characteristics, distinct CD8+ T-cell immune infiltration, and immunotherapy response. Gene set enrichment analysis (GSEA) showed that immune pathways such as allograft rejection, inflammatory response, interferon alpha and gamma response, and antigen processing and presentation were all positively activated in low-risk phenotype.ConclusionOur work gives an inspiration to explain the limited response for the current immune checkpoint inhibitors to UM. Besides, we constructed a novel gene signature to predict prognosis and immunotherapy responses, which may be regarded as a promising therapeutic target.

scholarly journals Clinical and immunological response to checkpoint therapy in renal cell carcinoma is associated with TCF1+ CD8 T-cells in the tumor

2021 ◽  
Author(s):  
Jennifer Carlisle ◽  
Caroline Jansen ◽  
Maria Cardenas ◽  
Ewelina Soierajska ◽  
Adriana Reyes Moon ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Renal Cell ◽  
Tumor Response ◽  
T Cell Response ◽  
Hla Dr

Abstract We investigated changes in T cell responses in the peripheral blood of patients with advanced renal cell carcinoma (RCC) after receiving immunotherapy. We found that a small proportion of both CD4 and CD8 cells activate and express the proliferation marker Ki67 and the activation markers HLA-DR and CD38. Patients who had the highest increase in these HLA-DR+CD38+ CD8 T cells after treatment had the best anti-tumor response. We studied these newly activated cells in more detail using flow cytometry and RNAseq and found that while these cells expanded in most patients, their phenotype did not drastically change during treatment. However, when we analyzed the TCR repertoire of these HLA-DR+CD38+CD8+ T cells, we found only patients who responded to the treatment had a burst of new clonotypes enter this pool of activated cells. Finally, we investigated how the T-cell response in the resected tumor months or years before receiving checkpoint therapy predicted later response to checkpoint therapy. Together, these data suggest that having a strong pre-existing immune response and immediate T cell response to checkpoint therapy is a predictor of anti-tumor response in patients with RCC.

scholarly journals Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
Cryptococcal Meningitis ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1994-1995 ◽  
Author(s):  
Masako Moriuchi ◽  
Hiroyuki Moriuchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Membrane Filter ◽  
Cd8 T Cell ◽  
Class I ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Permeable Membrane

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.

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 Relationship between PD-L1 expression, CD8+ T-cell infiltration and prognosis in intrahepatic cholangiocarcinoma patients

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Min Deng ◽  
Shao-Hua Li ◽  
Xu Fu ◽  
Xiao-Peng Yan ◽  
Jun Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Intrahepatic Cholangiocarcinoma ◽  
Patient Survival ◽  
Disease Free Survival ◽  
Cd8 T Cell ◽  
Future Research ◽  
Programmed Death ◽  
Expression Rate

Abstract Background Programmed death- ligand 1 (PD-L1) seems to be associated with the immune escape of tumors, and immunotherapy may be a favorable treatment for PD-L1-positive patients. We evaluated intrahepatic cholangiocarcinoma (ICC) specimens for their expression of PD-L1, infiltration of CD8+ T cells, and the relationship between these factors and patient survival. Methods In total, 69 resections of ICC were stained by immunohistochemistry for PD-L1, programmed death factor-1 (PD-1), and CD8+ T cells. CD8+ T-cell densities were analyzed both within tumors and at the tumor-stromal interface. Patient survival was predicted based on the PD-L1 status and CD8+ T-cell density. Results The expression rate of PD-L1 was 12% in cancer cells and 51% in interstitial cells. The expression rate of PD-1 was 30%, and the number of CD8+ T-cells increased with the increase of PD-L1 expression (p < 0.05). The expression of PD-L1 in the tumor was correlated with poor overall survival(OS) (p = 0.004), and the number of tumor and interstitial CD8+ T-cells was correlated with poor OS and disease-free survival (DFS) (All p < 0.001). Conclusions The expression of PD-L1 in the tumor is related to poor OS, and the number of tumor or interstitial CD8+ T-cells is related to poor OS and DFS. For patients who lose their chance of surgery, PD-L1 immunosuppressive therapy may be the focus of future research as a potential treatment.

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