scholarly journals TIM-3 as a Prognostic Marker and a Potential Immunotherapy Target in Human Malignant Tumors: A Meta-Analysis and Bioinformatics Validation

2021 ◽  
Vol 11 ◽  
Author(s):  
Kui Zang ◽  
Liangliang Hui ◽  
Min Wang ◽  
Ying Huang ◽  
Xingxing Zhu ◽  
...  
Keyword(s):  
Functional Analysis ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
T Cell Activation ◽  
Malignant Tumors ◽  
Killer Cell ◽  
Cell Lung Carcinoma ◽  
Cox Regression Analysis

BackgroundAs a novel immune checkpoint molecular, T-cell immunoglobulin mucin 3 (TIM-3) is emerging as a therapeutic target for cancer immunotherapy. However, the predictive role of TIM-3 in cancer remains largely undetermined. This study was designed to investigate the role of TIM-3 in cancer.MethodsPublications were searched using multiple databases. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. To further confirm the prognostic effect of TIM-3, The Cancer Genome Atlas (TCGA) data were applied. Functional analysis of TIM-3 was also investigated.Results28 studies with 7284 patients with malignant tumors were identified. Based on multivariate Cox regression analysis, TIM-3 was an independent prognostic indicator for poor overall survival (OS) (HR= 1.54, 95% CI = 1.19-1.98, P = 0.001). However, TIM-3 was not correlated with cancer-specific survival and disease-free survival (DFS). Particularly, TIM-3 showed a worse prognosis in non-small cell lung carcinoma and gastric cancer; but it showed a favorable prognosis in breast cancer. Functional analysis showed that TIM-3 was closely correlated with immune responses such as T-cell activation and natural killer cell-mediated cytotoxicity. Moreover, TIM-3 expression was found to be related to worse OS in 9491 TCGA patients (HR = 1.2, P < 0.001), but was not associated with DFS.ConclusionsTIM-3 was an independent prognostic factor. Meanwhile, TIM-3 played a crucial role in tumor immune responses. This supports TIM-3 as a promising target for cancer immunotherapy.

scholarly journals Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cheng-Tao Jiang ◽  
Kai-Ge Chen ◽  
An Liu ◽  
Hua Huang ◽  
Ya-Nan Fan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Noncovalent Interactions ◽  
Killer Cell ◽  
Antibody Immobilization ◽  
Effector Cells ◽  
Nanoparticle Surface

AbstractModulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

scholarly journals DNAJC10 correlates with tumor immune characteristics and predicts the prognosis of glioma patients

2022 ◽  
Author(s):  
Feng Liu ◽  
Zewei Tu ◽  
Junzhe Liu ◽  
Xiaoyan Long ◽  
Bing Xiao ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cox Regression ◽  
Quantitative Polymerase Chain Reaction ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Clinical Samples ◽  
Prognostic Role ◽  
Cox Regression Analysis

Background: The role of DNAJC10 in cancers have been reported but its function in glioma is not clear. We reveal the prognostic role and underlying functions of DNAJC10 in glioma in this study. Methods: Reverse Transcription and Quantitative Polymerase Chain Reaction (RT-qPCR) was used to quantify the relative DNAJC10 mRNA expression of clinical samples. Protein expressions of clinical samples were tested by Western blot. The overall survival (OS) of glioma patients with different DNAJC10 expression was compared by Kaplan-Meier method (two-sided log-rank test). Single-sample gene set enrichment analysis (ssGSEA) was used to estimate the immune cell infiltrations and immune-related function levels. The independent prognostic role of DNAJC10 was determined by univariate and multivariate Cox regression analysis. The DNAJC10-based nomogram model was established using multivariate Cox regression by R package “rms”. Results: Higher DNAJC10 is observed in gliomas and it’s upregulated in higher grade, IDH-wild, 1p/19q non-codeletion, MGMT unmethylated gliomas. Gliomas with higher DNAJC10 expression present poorer prognosis compared with low-DNAJC10 gliomas. The predictive accuracy of 1/3/5-OS of DNAJC10 is found stable and robust using time-dependent ROC model. Enrichment analysis recognized that T-cell activation and T-cell receptor signaling were enriched in higher DNAJC10 gliomas. Immune/stromal cell infiltrations, tumor mutation burden (TMB), copy Number Alteration (CNA) burden, and immune check-point genes were also positively correlated with DNAJC10 expression in gliomas. DNAJ10-based nomogram model was established and showed strong prognosis-predictive ability. Conclusion: Higher DNAJC10 expression correlates with poor prognosis of glioma and it was a potential prognostic biomarker for glioma.

scholarly journals Releasing the Brake: Targeting Cbl-b to Enhance Lymphocyte Effector Functions

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Stephanie Wallner ◽  
Thomas Gruber ◽  
Gottfried Baier ◽  
Dominik Wolf
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Malignant Tumors ◽  
Current Knowledge ◽  
Negative Regulator ◽  
Therapeutic Concept ◽  
Therapeutic Implications

The E3 ubiquitin ligase Cbl-b is an established nonredundant negative regulator of T-cell activation. Cbl-b fine-tunes the activation threshold of T cells and uncouples T cells from their vital need of a costimulatory signal to mount a productive immune response. Accordingly, mice deficient incblbare prone to autoimmunity and reject tumors. The latter has been described to be mediatedviaCD8+T cells, which are hyperactive and more abundant in shrinking tumors ofcblb-deficient animals. This might at least also in part be mediated by resistance ofcblb-deficient T cells to negative cues exerted by tumor-associated immuno-suppressive factors, such as TGF-βand regulatory T cells (Treg). Experiments usingcblb-deficient T cells either alone or in combination with vaccines validate the therapeutic concept of enhancing the efficacy of adoptively transferred lymphocytes to treat malignant tumors. This paper summarizes the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy.

scholarly journals B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriela Sarti Kinker ◽  
Glauco Akelinghton Freire Vitiello ◽  
Wallax Augusto Silva Ferreira ◽  
Alexandre Silva Chaves ◽  
Vladmir Cláudio Cordeiro de Lima ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Plasma Cells ◽  
Peripheral Tissues ◽  
Effector Functions

The immune system plays a crucial role in cancer development either by fostering tumor growth or destroying tumor cells, which has open new avenues for cancer immunotherapy. It was only over the last decade that the role of B cells in controlling anti-tumor immune responses in the tumor milieu has begun to be appreciated. B and plasma cells can exert anti-tumor effects through antibody-dependent cell cytotoxicity (ADCC) and activation of the complement cascade, even though their effector functions extend beyond the classical humoral immunity. In tumor tissues, B cells can be found in lymphoid aggregates, known as tertiary lymphoid structures (TLSs), well-organized non-encapsulated structures composed of immune and stromal cells. These structures reflect a process of lymphoid neogenesis occurring in peripheral tissues upon long-lasting exposure to inflammatory signals. The TLS provides an area of intense B cell antigen presentation that can lead to optimal T cell activation and effector functions, as well as the generation of effector B cells, which can be further differentiated in either antibody-secreting plasma cells or memory B cells. Of clinical interest, the crosstalk between B cells and antigen-experienced and exhausted CD8+ T cells within mature TLS was recently associated with improved response to immune checkpoint blockade (ICB) in melanoma, sarcoma and lung cancer. Otherwise, B cells sparsely distributed in the tumor microenvironment or organized in immature TLSs were found to exert immune-regulatory functions, inhibiting anti-tumor immunity through the secretion of anti-inflammatory cytokines. Such phenotype might arise when B cells interact with malignant cells rather than T and dendritic cells. Differences in the spatial distribution likely underlie discrepancies between the role of B cells inferred from human samples or mouse models. Many fast-growing orthotopic tumors develop a malignant cell-rich bulk with reduced stroma and are devoid of TLSs, which highlights the importance of carefully selecting pre-clinical models. In summary, strategies that promote TLS formation in close proximity to tumor cells are likely to favor immunotherapy responses. Here, the cellular and molecular programs coordinating B cell development, activation and organization within TLSs will be reviewed, focusing on their translational relevance to cancer immunotherapy.

scholarly journals Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

2021 ◽  
Vol 9 (1) ◽  
pp. e001615
Author(s):  
Rachel A Woolaver ◽  
Xiaoguang Wang ◽  
Alexandra L Krinsky ◽  
Brittany C Waschke ◽  
Samantha M Y Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Single Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Tcr Repertoire ◽  
Underlying Mechanisms ◽  
Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

Modulation of T-Cell Functions in KIR2DL3 (CD158b) Transgenic Mice

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2396-2402 ◽  
Author(s):  
Anna Cambiaggi ◽  
Sylvie Darche ◽  
Sophie Guia ◽  
Philippe Kourilsky ◽  
Jean-Pierre Abastado ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Activation ◽  
Cell Activation ◽  
Killer Cell ◽  
In Vitro Proliferation ◽  
Cell Functions ◽  
Double Transgenic Mice

In humans, a minor subset of T cells express killer cell Ig-like receptors (KIRs) at their surface. In vitro data obtained with KIR+ β and γδ T-cell clones showed that engagement of KIR molecules can extinguish T-cell activation signals induced via the CD3/T-cell receptor (TCR) complex. We analyzed the T-cell compartment in mice transgenic for KIR2DL3 (Tg-KIR2DL3), an inhibitory receptor for HLA-Cw3. As expected, mixed lymphocyte reaction and anti-CD3 monoclonal antibody (MoAb)-redirected cytotoxicity exerted by freshly isolated splenocytes can be inhibited by engagement of transgenic KIR2DL3 molecules. In contrast, antigen and anti-CD3 MoAb-induced cytotoxicity exerted by alloreactive cytotoxic T lymphocytes cannot be inhibited by KIR2DL3 engagement. In double transgenic mice, Tg-KIR2DL3 × Tg-HLA-Cw3, no alteration of thymic differentiation could be documented. Immunization of double transgenic mice with Hen egg white lysozime (HEL) or Pigeon Cytochrome-C (PCC) was indistinguishable from immunization of control mice, as judged by recall antigen-induced in vitro proliferation and TCR repertoire analysis. These results indicate that KIR effect on T cells varies upon cell activation stage and show unexpected complexity in the biological function of KIRs in vivo.

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