scholarly journals The Immune Profile of Pituitary Adenomas and a Novel Immune Classification for Predicting Immunotherapy Responsiveness

2020 ◽  
Vol 105 (9) ◽  
pp. e3207-e3223
Author(s):  
Zihao Wang ◽  
Xiaopeng Guo ◽  
Lu Gao ◽  
Kan Deng ◽  
Wei Lian ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Pituitary Adenomas ◽  
Tumor Development ◽  
Immune Microenvironment ◽  
Immune Profile ◽  
Programmed Cell Death 1 ◽  
Tumor Immune Microenvironment ◽  
Specific Protease ◽  
Cell Death Protein

Abstract Context The tumor immune microenvironment is associated with clinical outcomes and immunotherapy responsiveness. Objective To investigate the intratumoral immune profile of pituitary adenomas (PAs) and its clinical relevance and to explore a novel immune classification for predicting immunotherapy responsiveness. Design, Patients, and Methods The transcriptomic data from 259 PAs and 20 normal pituitaries were included for analysis. The ImmuCellAI algorithm was used to estimate the abundance of 24 types of tumor-infiltrating immune cells (TIICs) and the expression of immune checkpoint molecules (ICMs). Results The distributions of TIICs differed between PAs and normal pituitaries and varied among PA subtypes. T cells dominated the immune microenvironment across all subtypes of PAs. The tumor size and patient age were correlated with the TIIC abundance, and the ubiquitin-specific protease 8 (USP8) mutation in corticotroph adenomas influenced the intratumoral TIIC distributions. Three immune clusters were identified across PAs based on the TIIC distributions. Each cluster of PAs showed unique features of ICM expression that were correlated with distinct pathways related to tumor development and progression. CTLA4/CD86 expression was upregulated in cluster 1, whereas programmed cell death protein 1/programmed cell death 1 ligand 2 (PD1/PD-L2) expression was upregulated in cluster 2. Clusters 1 and 2 exhibited a “hot” immune microenvironment and were predicted to exhibit higher immunotherapy responsiveness than cluster 3, which exhibited an overall “cold” immune microenvironment. Conclusions We summarized the immune profile of PAs and identified 3 novel immune clusters. These findings establish a foundation for further immune studies on PAs and provide new insights into immunotherapy strategies for PAs.

scholarly journals The Evolving Landscape of Biomarkers for Anti-PD-1 or Anti-PD-L1 Therapy

2019 ◽  
Vol 8 (10) ◽  
pp. 1534 ◽  
Author(s):  
Antje Tunger ◽  
Ulrich Sommer ◽  
Rebekka Wehner ◽  
Anne Sophie Kubasch ◽  
Marc-Oliver Grimm ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Tumor Regression ◽  
Treatment Resistance ◽  
Immune Monitoring ◽  
Small Cell Lung ◽  
Tumor Patients ◽  
Programmed Cell Death 1 ◽  
Promising Treatment ◽  
Cell Death Protein

The administration of antibodies blocking the immune checkpoint molecules programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) has evolved as a very promising treatment option for cancer patients. PD-1/PD-L1 inhibition has significantly enhanced expansion, cytokine secretion, and cytotoxic activity of CD4+ and CD8+ T lymphocytes, resulting in enhanced antitumor responses. Anti-PD-1 or anti-PD-L1 therapy has induced tumor regression and improved clinical outcome in patients with different tumor entities, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. These findings led to the approval of various anti-PD-1 or anti-PD-L1 antibodies for the treatment of tumor patients. However, the majority of patients have failed to respond to this treatment modality. Comprehensive immune monitoring of clinical trials led to the identification of potential biomarkers distinguishing between responders and non-responders, the discovery of modes of treatment resistance, and the design of improved immunotherapeutic strategies. In this review article, we summarize the evolving landscape of biomarkers for anti-PD-1 or anti-PD-L1 therapy.

scholarly journals PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

2021 ◽  
Vol 22 (21) ◽  
pp. 11797
Author(s):  
Ewa Surmiak ◽  
Katarzyna Magiera-Mularz ◽  
Bogdan Musielak ◽  
Damian Muszak ◽  
Justyna Kocik-Krol ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint Blockade ◽  
Mechanisms Of Action ◽  
In Vitro Bioactivity ◽  
Drug Candidates ◽  
Programmed Cell Death 1 ◽  
Blocking Activity ◽  
Cell Death Protein

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.

scholarly journals Immunophenotypes Based on the Tumor Immune Microenvironment Allow for Unsupervised Penile Cancer Patient Stratification

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1796 ◽  
Author(s):  
Chengbiao Chu ◽  
Kai Yao ◽  
Jiangli Lu ◽  
Yijun Zhang ◽  
Keming Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cytotoxic T Lymphocyte ◽  
Granzyme B ◽  
Expression Patterns ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

The tumor immune microenvironment (TIME) plays an important role in penile squamous cell carcinoma (peSCC) pathogenesis. Here, the immunophenotype of the TIME in peSCC was determined by integrating the expression patterns of immune checkpoints (programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and Siglec-15) and the components of tumor-infiltrating lymphocytes, including CD8+ or Granzyme B+ T cells, FOXP3+ regulatory T cells, and CD68+ or CD206+ macrophages, in 178 patients. A high density of Granzyme B, FOXP3, CD68, CD206, PD-1, and CTLA-4 was associated with better disease-specific survival (DSS). The patients with diffuse PD-L1 tumor cell expression had worse prognoses than those with marginal or negative PD-L1 expression. Four immunophenotypes were identified by unsupervised clustering analysis, based on certain immune markers, which were associated with DSS and lymph node metastasis (LNM) in peSCC. There was no significant relationship between the immunophenotypes and high-risk human papillomavirus (hrHPV) infection. However, the hrHPV–positive peSCC exhibited a higher density of stromal Granzyme B and intratumoral PD-1 than the hrHPV–negative tumors (p = 0.049 and 0.002, respectively). In conclusion, the immunophenotypes of peSCC were of great value in predicting LNM and prognosis, and may provide support for clinical stratification management and immunotherapy intervention.

scholarly journals Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer

Kidney360 ◽  
2020 ◽  
Vol 1 (5) ◽  
pp. 376-388
Author(s):  
Josephine F. Trott ◽  
Omran Abu Aboud ◽  
Bridget McLaughlin ◽  
Katie L. Anderson ◽  
Jaime F. Modiano ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Kidney Cancer ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
The United States ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Programmed Cell Death 1 ◽  
Anti Cancer ◽  
Cell Death Protein

BackgroundKidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer.MethodsIn this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti–programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies.ResultsWe demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) Naprt expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors.ConclusionsThis study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.

scholarly journals Maprotiline Prompt the Anti-tumor Effect by Inhibiting the PD-L1 in Mice Burdened Melanoma

2021 ◽  
Author(s):  
Tiesuo Zhao ◽  
Yang Li ◽  
Miaomiao Liu ◽  
Lin Zhou ◽  
Zunge Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Tumor Tissues ◽  
Programmed Cell Death 1 ◽  
Tetracyclic Antidepressant ◽  
And Migration ◽  
Cell Death Protein

Abstract Programmed cell death 1 ligand 1(PD-L1) binds with programmed cell death protein 1 (PD-1) to inhibit the responses of T cells. PD-L1 is significantly upregulated on tumor cells and blocking the PD-L1/PD-1 signal has become an important target of immunotherapy in clinic. At present, some old drugs of non-antitumor have been found that could play the effect of anti-tumor. Maprotiline, as a tetracyclic antidepressant, has been widely used for treating mental depression. Here, we study the anti-tumor effect of maprotiline by strengthening the immune response of mice. In vitro, treatment with maprotiline inhibits the proliferation and migration of B16 cells, increases the cell apoptosis. Importantly, treatment with maprotiline reduces the expression of PD-L1 in tumor tissue, prompts the ratios of CD4+ T cells, CD8+ T cells and NK cells in spleens, increases the infiltration of CD4+ and CD8+ T cells in tumor-tissues. In brief, we determine that maprotiline could prompt the anti-tumor immune response by inhibiting the PD-L1 in mice. This study may find a new inhibitor of PD-L1, which provides a new drug treated tumor in clinical.

PD-L1 expression level in different thymoma stages and thymic carcinoma: a meta-analysis

2020 ◽  
Vol 106 (4) ◽  
pp. 306-311
Author(s):  
Hua-Fei Chen ◽  
Li-Xin Wu ◽  
Xiao-Feng Li ◽  
You-Cai Zhu ◽  
Wei-Wei Pan ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Thymic Carcinoma ◽  
Meta Analysis ◽  
Type A ◽  
Expression Level ◽  
Programmed Cell Death 1 ◽  
Significant Difference ◽  
Cell Death Protein ◽  
Potential Use

Background: The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. Methods: We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. Results: No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high ( I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity ( I2 = 55%). Conclusion: PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.

scholarly journals Cisplatin remodels the tumor immune microenvironment via the transcription factor EB in ovarian cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wei Liu ◽  
Yanqiu Wang ◽  
Yunkai Xie ◽  
Tianyu Dai ◽  
Mingjun Fan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Transcription Factor ◽  
Programmed Cell Death ◽  
Nuclear Translocation ◽  
Cytolytic Activity ◽  
Immune Microenvironment ◽  
Tissue Samples ◽  
Tumor Immune Microenvironment ◽  
Transcription Factor Eb

AbstractThe mortality rate of ovarian cancer (OC) remains the highest among all gynecological malignancies. Platinum-based chemotherapies are effective in treating most OC cases. However, chemoresistance is still a major challenge for successful OC treatments. Emerging evidence has highlighted that the modulation of the tumor immune microenvironment is involved in chemoresistance, but the mechanism remains unclear. This study aimed to investigate whether resistance to cisplatin (CDDP), the standard treatment for OC, is due to the remodeling of the tumor immune microenvironment by the transcription factor EB (TFEB). We hypothesized that TFEB is not essential for tumor survival but is associated with CDDP resistance. We collected 20 tissue samples of OC patients who had not undergone chemotherapy or radiotherapy prior to surgery. We cultured OC cell lines and performed cell transfection and assays as well as analytical, fluorescence microscopy, and immunohistochemical techniques to explore a novel function of TFEB in remodeling the tumor immune microenvironment in OC. We found a positive correlation between TFEB and programmed cell death-ligand 1 (PD-L1), PD-L2, and HLA-A expression in OC cells and tissues. We also found that CDDP treatment induced TFEB nuclear translocation, thus increasing PD-L1 and PD-L2 expression to foster an immunosuppressive tumor microenvironment, which mediates tumor immune evasion and drug resistance. Interestingly, TFEB also regulated HLA-A expression, which increases the tumor immunogenicity of OC. Finally, in a syngenic murine model of OC, we observed the therapeutic benefit of CDDP plus programmed cell death-1 (PD-1) inhibitor, which enhanced the cytolytic activity of CD8+ T cells and inhibited tumor growth. Our study illustrates the important role of TFEB in regulating the tumor immune microenvironment in OC.

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