Abstract 713: Upregulation of immune checkpoint molecules on Treg cells in tumor microenvironment reinforces immune exhaustion in cancer patients

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.

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Impact of immune checkpoint molecules on FoxP3+ Treg cells and related cytokines in patients with acute and chronic brucellosis

BMC Infectious Diseases ◽

10.1186/s12879-021-06730-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hua-Li Sun ◽

Xiu-Fang Du ◽

Yun-Xia Tang ◽

Guo-Qiang Li ◽

Si-Yuan Yang ◽

...

Keyword(s):

T Cells ◽

Immune Checkpoint ◽

Treg Cells ◽

Shanxi Province ◽

Healthy Controls ◽

Chronic Patients ◽

Immune Checkpoint Molecules ◽

Significant Difference ◽

Acute Patients ◽

Tgf Β1

Abstract Background The immunoregulatory functions of regulatory T cells (Tregs) in the development and progression of some chronic infectious diseases are mediated by immune checkpoint molecules and immunosuppressive cytokines. However, little is known about the immunosuppressive functions of Tregs in human brucellosis, which is a major burden in low-income countries. In this study, expressions of immune checkpoint molecules and Treg-related cytokines in patients with acute and chronic Brucella infection were evaluated to explore their impact at different stages of infection. Methods Forty patients with acute brucellosis and 19 patients with chronic brucellosis admitted to the Third People’s Hospital of Linfen in Shanxi Province between August 2016 and November 2017 were enrolled. Serum and peripheral blood mononuclear cells were isolated from patients before antibiotic treatment and from 30 healthy subjects. The frequency of Tregs (CD4+ CD25+ FoxP3+ T cells) and expression of CTLA-4, GITR, and PD-1 on Treg cells were detected by flow cytometry. Levels of Treg-related cytokines, including IL-35, TGF-β1, and IL-10, were measured by customised multiplex cytokine assays using the Luminex platform. Results The frequency of Tregs was higher in chronic patients than in healthy controls (P = 0.026) and acute patients (P = 0.042); The frequency of CTLA-4+ Tregs in chronic patients was significantly higher than that in healthy controls (P = 0.011). The frequencies of GITR+ and PD-1+ Tregs were significantly higher in acute and chronic patients than in healthy controls (P < 0.05), with no significant difference between the acute and chronic groups (all P > 0.05). Serum TGF-β1 levels were higher in chronic patients (P = 0.029) and serum IL-10 levels were higher in acute patients (P = 0.033) than in healthy controls. We detected weak correlations between serum TGF-β1 levels and the frequencies of Tregs (R = 0.309, P = 0.031) and CTLA-4+ Tregs (R = 0.302, P = 0.035). Conclusions Treg cell immunity is involved in the chronicity of Brucella infection and indicates the implication of Tregs in the prognosis of brucellosis. CTLA-4 and TGF-β1 may contribute to Tregs-mediated immunosuppression in the chronic infection stage of a Brucella infection.

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

Cellular and Molecular Life Sciences ◽

10.1007/s00018-019-03362-4 ◽

2019 ◽

Vol 77 (17) ◽

pp. 3441-3452 ◽

Cited By ~ 3

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.

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Abstract CT053: Intratumoral coxsackievirus A21 increases immune-cell infiltrates and upregulates immune-checkpoint molecules in the tumor microenvironment of advanced melanoma patients: phase II CALM extension study

10.1158/1538-7445.am2016-ct053 ◽

2016 ◽

Cited By ~ 1

Author(s):

Robert Andtbacka ◽

Brendan Curti ◽

Sigrun Hallmeyer ◽

Zipei Peng ◽

Christopher Paustian ◽

...

Keyword(s):

Tumor Microenvironment ◽

Phase Ii ◽

Immune Checkpoint ◽

Immune Cell ◽

Advanced Melanoma ◽

Extension Study ◽

Immune Checkpoint Molecules ◽

Coxsackievirus A21 ◽

Melanoma Patients ◽

Immune Cell Infiltrates

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Unveiling a Critical Role of Thrombin in Enhanced CD8+ T Cell Response to Cancer

Blood ◽

10.1182/blood-2019-128739 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4918-4918

Author(s):

Rachel Cantrell ◽

Leah A. Rosenfeldt ◽

Duaa Mureb ◽

Balkrishan Sharma ◽

Alexey Revenko ◽

...

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Cancer Patients ◽

Immune Checkpoint ◽

Thrombin Generation ◽

Critical Role ◽

Cd8 T Cell ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

A serious and life-threatening cancer-associated sequelae is venous thromboembolism (VTE). Indeed, VTE is the second leading cause of death in cancer patients, second only to the malignancy itself. Cancer patients with VTE or at high risk for VTE are generally treated with anticoagulants, which limit thrombin generation. While it's been widely accepted that thrombin plays a role in cancer progression, the effects thrombin has on other cell types within the tumor microenvironment (TME) have not been thoroughly studied. An understudied role of thrombin may be found in its ability to drive T cell functions. Recently, we have identified thrombin as a potential enhancer of CD8+ T cell effector functions by signaling through the protease activated receptor 1 (PAR-1). Our preliminary data shows that thrombin increases CD8+ T cell survival in a PAR-1 dependent fashion. CD8+ tumor infiltrating lymphocytes (TILs) play a critical role in tumor clearance through their cytolytic and anti-tumor cytokine producing capacity. However, the hostile tumor microenvironment (TME) promotes a gradual reduction in CD8+ TIL capacity to produce cytokines and kill targets. Specific components of the TME, including PDL1 expression, are associated with loss of T cell functionality. A promising strategy to block the interaction of CD8+ TILs and the inhibitory TME components is immune checkpoint inhibition (ICI) therapy, as shown by effective blockade of PD1 signaling by anti-PD1 antibodies. However, these ICI therapies leave many patients unresponsive, highlighting the necessity to uncover additional underlying mechanisms involved in modulating CD8+ T cell responses against cancer. Our preliminary findings lead us to hypothesize that thrombin, in conjunction with PD1 blockade, may work in synergy to promote CD8+ T cell killing of tumors. Consistent with our hypothesis, preliminary results suggest that thrombin is necessary for a robust anti-tumor immune response following ICI in vivo. Here, cohorts of C57BL/6 mice with low or normal circulating prothrombin levels bearing B16 tumors were treated with an anti-PD1 antibody or control IgG. Anti-PD1 therapy significantly limited tumor growth in mice with normal prothrombin levels, but had no impact on tumor growth in mice with low prothrombin levels. A major implication of our findings is that limiting thrombin generation with anticoagulants may be detrimental in the context of immune checkpoint inhibition treatment. Better defining the potential risk of reducing ICI efficacy by concurrent treatment with anticoagulants will require a detailed understanding of the role thrombin plays in cancer immunobiology. Disclosures Revenko: Ionis Pharmaceuticals: Employment. Monia:Ionis Pharmaceuticals: Employment. Palumbo:Ionis Pharmaceuticals: Research Funding.

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.608969 ◽

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.

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