Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules

2019 ◽  
Vol 71 (4) ◽  
pp. 753-762 ◽  
Author(s):  
Guoying Zhou ◽  
Dave Sprengers ◽  
Shanta Mancham ◽  
Remco Erkens ◽  
Patrick P.C. Boor ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Ex Vivo ◽  
Immune Checkpoint Molecules ◽  
Immunosuppressive Tumor Microenvironment

scholarly journals Age and Mutations as Predictors of the Response to Immunotherapy in Head and Neck Squamous Cell Cancer

2020 ◽  
Vol 8 ◽  
Author(s):  
Yueming Zhang ◽  
Anqi Lin ◽  
Yonghe Li ◽  
Weimin Ding ◽  
Hui Meng ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Head And Neck ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Cox Regression ◽  
Cell Cancer ◽  
Cancer Center ◽  
Cox Regression Analysis ◽  
Immune Checkpoint Molecules ◽  
Immunosuppressive Tumor Microenvironment

The immunosuppressive tumor microenvironment plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSC). Compared to traditional chemoradiotherapy, immune checkpoint inhibitors (ICIs) have become increasingly important in HNSC therapy. Prior studies linked the efficacy of ICIs to PD-L1, microsatellite instability (MSI), HPV infection, tumor mutation burden (TMB), and tumor lymphocyte infiltration in patients with HNSC, but further verification is needed. Additional predictors are needed to recognize HNSC patients with a good response to ICIs. We collected the clinical information and mutation data of HNSC patients from Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA) databases to generate two clinical cohorts. The MSKCC cohort was used to recognize predictors related to the efficacy of ICIs, and the TCGA cohort was used to further examine the immune microenvironment features and signaling pathways that are significantly enriched in the subgroups of predictors. Multivariate Cox regression analysis indicated that age (HR = 0.50, p = 0.014) and ARID1A (HR = 0.13, p = 0.048), PIK3CA (HR = 0.45, p = 0.021), and TP53 (HR = 1.82, p = 0.035) mutations were potential predictors for ICI efficacy in HNSC patients. Age > 65 years and ARID1A or PIK3CA mutations correlated with good overall survival (OS). TP53 mutant-type (MT) patients experienced a worse prognosis than TP53 wild-type (WT) patients. The subgroups associated with a good prognosis (age > 65 years, ARID1A-MT, and PIK3CA-MT) universally had a high TMB and increased expression of immune checkpoint molecules. Although TP53-MT was associated with a high TMB, the expression of most immune checkpoint molecules and immune-related genes was lower in TP53-MT patients than TP53-WT patients, which may reflect low immunogenicity. Pathways related to the immunosuppressive tumor microenvironment were mostly enriched in the subgroups associated with a poor prognosis (age ≤ 65 years, low TMB, ARID1A-WT, PIK3CA-WT, and TP53-MT). In conclusion, the factors age > 65 years, PIK3CA-MT, and ARID1A-MT predicted favorable efficacy for ICI treatment in HNSC patients, and TP53 mutation was a negative predictor.

scholarly journals Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment

2017 ◽  
Vol 200 (1) ◽  
pp. 347-354 ◽  
Author(s):  
Mark A. J. Gorris ◽  
Altuna Halilovic ◽  
Katrin Rabold ◽  
Anne van Duffelen ◽  
Iresha N. Wickramasinghe ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Simultaneous Detection ◽  
Immune Checkpoint Molecules

scholarly journals The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Nádia Ghinelli Amôr ◽  
Paulo Sérgio da Silva Santos ◽  
Ana Paula Campanelli
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Molecules

Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

scholarly journals Modulation of SRSF2 expression reverses the exhaustion of TILs via the epigenetic regulation of immune checkpoint molecules

2019 ◽  
Vol 77 (17) ◽  
pp. 3441-3452 ◽  
Author(s):  
Ziqiang Wang ◽  
Kun Li ◽  
Wei Chen ◽  
Xiaoxia Wang ◽  
Yikun Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoints ◽  
Gene Promoters ◽  
Immune Checkpoint Molecules ◽  
Elevated Expression ◽  
Infiltrating Lymphocytes ◽  
Checkpoint Genes

AbstractThe elevated expression of immune checkpoints by the tumor microenvironment is associated with poor prognosis in several cancers due to the exhaustion of tumor-infiltrating lymphocytes (TILs), and the effective suppression of the expression of these genes is key to reversing the exhaustion of TILs. Herein, we determined that serine/arginine-rich splicing factor 2 (SRSF2) is a target for blocking the tumor microenvironment-associated immunosuppressive effects. We found that the expression of SRSF2 was increased in exhausted T cells and that SRSF2 was involved in multiple immune checkpoint molecules mediating TILs’ exhaustion. Furthermore, SRSF2 was revealed to regulate the transcription of these immune checkpoint genes by associating with an acyl-transferases P300/CBP complex and altering the H3K27Ac level near these genes, thereafter influencing the recruitment of signal transducer and activator of transcription 3 (STAT3) to these gene promoters. Collectively, our data indicated that SRSF2 functions as a modulator of the anti-tumor response of T cells and may be a therapeutic target for reversing the exhaustion of TILs.

scholarly journals Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yalei Zhang ◽  
Ye Li ◽  
Kun Chen ◽  
Ling Qian ◽  
Peng Wang
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Tumor Resistance ◽  
Systemic Delivery ◽  
Future Directions ◽  
Immunosuppressive Tumor Microenvironment ◽  
Proinflammatory Factors

AbstractIt has been intensively reported that the immunosuppressive tumor microenvironment (TME) results in tumor resistance to immunotherapy, especially immune checkpoint blockade and chimeric T cell antigen therapy. As an emerging therapeutic agent, oncolytic viruses (OVs) can specifically kill malignant cells and modify immune and non-immune TME components through their intrinsic properties or genetically incorporated with TME regulators. Strategies of manipulating OVs against the immunosuppressive TME include serving as a cancer vaccine, expressing proinflammatory factors and immune checkpoint inhibitors, and regulating nonimmune stromal constituents. In this review, we summarized the mechanisms and applications of OVs against the immunosuppressive TME, and strategies of OVs in combination with immunotherapy. We also introduced future directions to achieve efficient clinical translation including optimization of preclinical models that simulate the human TME and achieving systemic delivery of OVs.

scholarly journals Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1960
Author(s):  
Tsubasa Miyazaki ◽  
Eiichi Ishikawa ◽  
Narushi Sugii ◽  
Masahide Matsuda
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Malignant Tumors ◽  
Suppressor Cells ◽  
Treatment Resistance ◽  
Glioma Initiating Cells ◽  
Programmed Cell Death 1 ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Tumor Microenvironment ◽  
Immunosuppressive Cells

Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells—including M2-type macrophages and myeloid-derived suppressor cells—that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.

The lipid platform increases the activity of STING agonists to synergize checkpoint blockade therapy against melanoma

2021 ◽  
Author(s):  
Kesang Li ◽  
Yingyi Ye ◽  
Liqin Liu ◽  
Qian Sha ◽  
Xiaolu Wang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Blockade ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Immunosuppressive Tumor Microenvironment

The response rate to PD-1/PD-L1 immune checkpoint inhibition (ICI) therapy in melanoma remains low due to the immunosuppressive tumor microenvironment.

scholarly journals CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001136
Author(s):  
Moran Yang ◽  
Jiaqi Lu ◽  
Guodong Zhang ◽  
Yiying Wang ◽  
Mengdi He ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
B Cells ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Ex Vivo ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Grade ◽  
Serous Ovarian Cancer

BackgroundMost patients with high-grade serous ovarian cancer (HGSC) lack an effective response to immune checkpoint blockade, highlighting the need for more knowledge about what is required for successful treatment. As follicular cytotoxic CXCR5+CD8+ T cells are maintained by reinvigoration by immune checkpoint blockade in tumors, we attempted to reveal the relationship between CXCR5+CD8+ T cells and the tumor microenvironment to predict immunotherapy responses in HGSC.Methods264 patients with HGSC from two cohorts and 340 HGSC cases from The Cancer Genome Atlas cohort were enrolled. Ex vivo and in vivo studies were conducted with human HGSC tumors and murine tumor models. The spatial correlation between CXC-chemokine ligand 13 (CXCL13), CXCR5, CD8, and CD20 was evaluated by immunohistochemistry and immunofluorescence. Survival was compared between different subsets of patients using Kaplan-Meier analysis. The therapeutic effect of CXCL13 and programmed cell death-1 (PD-1) blockade was validated using human HGSC tumors and murine models.ResultsHigh CXCL13 expression was associated with prolonged survival. Tumors with high CXCL13 expression exhibited increased infiltration of activated and CXCR5-expressing CD8+ T cells. Incubation with CXCL13 facilitated expansion and activation of CXCR5+CD8+ T cells ex vivo. CXCR5+CD8+ T cells appeared in closer proximity to CXCL13 in tumors and chemotaxis towards CXCL13 in vitro. The combination of CXCL13, CXCR5, and CD8+ T cells was an independent predictor for survival. In addition, CXCL13 was associated with clusters of CD20+ B cells. CD20+ B cells predicted better patient survival in the presence of CXCL13. Histological evaluation highlighted colocalization of CXCL13 with tertiary lymphoid structures (TLSs). TLSs carried prognostic benefit only in the presence of CXCL13. CXCL13 in combination with anti-PD-1 therapy retarded tumor growth in a CD8+ T-cell-dependent manner, resulting in increased infiltration of cytotoxic CD8+ T cells and CXCR5+CD8+ T cells.ConclusionsThese data define a critical role of CXCL13 in shaping antitumor microenvironment by facilitating the maintenance of CXCR5+CD8+ T cells in TLSs and support a clinical investigation for a combination of CXCL13 and PD-1 blockade therapy in HGSC.

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