scholarly journals The Periphery of Salivary Gland Carcinoma Tumors Reveals a PD-L1/PD-1 Biomarker Niche for the Evaluation of Disease Severity and Tumor—Immune System Interplay

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 97
Author(s):  
Martin Kuchar ◽  
Zuzana Strizova ◽  
Linda Capkova ◽  
Martin Komarc ◽  
Jiri Skrivan ◽  
...  
Keyword(s):  
Cell Death ◽  
Salivary Gland ◽  
Tumor Cells ◽  
Disease Severity ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Periphery ◽  
Tumor Center ◽  
Programed Cell Death ◽  
Cell Death Protein

The treatment options for patients with advanced salivary gland cancers (SGCs) are limited. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, the response to ICI immunotherapy is largely driven by the immune cell signatures within the tumor tissue and the para-tumoral tissue compartments. To date, there are no data on the expression of programed cell death protein-1/programed cell death protein-ligand 1 (PD-1/PD-L1) in SGC, which may enable the implementation of ICI immunotherapy for this disease. Thus, we performed an immunohistochemical analysis of PD-1 and PD-L1 expression in tumor cells and tumor-infiltrating immune cells (TIICs) in the tumor center and periphery of 62 SGC patients. The tumor periphery showed significantly higher expression of PD-L1 in tumor cells than in TIICs. Moreover, peripheral TIICs had significantly higher PD-1 expression than peripheral tumor cells. PD-1-positive tumor cells were detected exclusively in the tumor center of high-grade tumors, and most importantly, the presence of lymph node (LN) metastases and primary tumor stage significantly correlated with the presence of PD-L1-positive tumor cells in the tumor periphery. The PD-1/PD-L1 molecular signatures in SGC are clustered predominantly in the tumor periphery, reflect disease severity, and may predict the response to ICI immunotherapy in SGC patients.

scholarly journals How Phosphatidylserine Is Exposed on Tumor Cells Determines The Tumor’s Microenvironment and the Success or Failure of Checkpoint Therapy

2021 ◽  
Author(s):  
James Randall Kennedy
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mitotic Cell ◽  
Continuous Growth ◽  
Inflammatory Microenvironment ◽  
A Cell ◽  
Programed Cell Death

Abstract One constant in all malignant somatic tumors is their continuous growth and it is hypothesized that there are only two types of cell mutations that can cause this and that their microenvironments are determined by how those mutated cells eventually die and by how phosphatidylserine (PS) is exposed on their surface. When a mutation in a cell causes its rate of mitotic cell division to continuously exceed the rate necessary for its replacement after its programed cell death (PCD) a continuously growing tumor will form and all of the tumor cells will expose PS by the Xkr8 transmembrane scramblase molecule when they die causing an inflammatory and immune suppressive microenvironment. When a mutation in a cell eliminates PCD a continuous tumor growth begins because all those cells will continue dividing until they die a senescent death where PS is exposed by the TMEM16F scramblase molecule and causes an inflammatory microenvironment. Inflammation stresses somatic cells to expose checkpoint molecules (CPMs) on them and on immune cells that could potentially eliminate them. Only in tumors where PCD has been eliminated will CPM be exposed and only in them will immune checkpoint inhibitors (ICIs) be effective.

scholarly journals Fas-Fas Ligand Interplay in the Periphery of Salivary Gland Carcinomas as a New Checkpoint Predictor for Disease Severity and Immunotherapy Response

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 402
Author(s):  
Zuzana Strizova ◽  
Martin Kuchar ◽  
Linda Capkova ◽  
Martin Komarc ◽  
Jiri Skrivan ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Tumor Cells ◽  
Immune Cells ◽  
Fas Ligand ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Tumor Stage ◽  
Tumor Periphery ◽  
Salivary Gland Carcinomas ◽  
Induced Apoptosis

Salivary gland carcinomas (SGCs) are extremely morphologically heterogeneous, and treatment options for this disease are limited. Immunotherapy with immune checkpoint inhibitors (ICIs) represents a revolutionary treatment approach. However, SGCs remain largely resistant to this therapy. An increasing body of evidence suggests that resistance to ICI therapy is modulated by the Fas (CD95)–Fas ligand (FasL, CD178) interplay between tumor cells and immune cells. In this study, we examined the Fas–FasL interplay between tumor cells and tumor-infiltrating immune cells (TIICs) in the center and periphery of SGCs from 62 patients. We found that the Fas-expressing tumor cells accumulated in the center of SGC tumors with increasing tumor stage. Furthermore, this accumulation occurred regardless of the presence of TIICs expressing high levels of FasL. On the contrary, a loss of Fas-expressing TIICs with increasing tumor stage was found in the tumor periphery, whereas FasL expression in tumor cells in the tumor periphery correlated with tumor stage. These data suggest that SGC cells are resistant to FasL-induced apoptosis by TIICs but could utilize FasL to eliminate these cells in high-stage tumors to provide resistance to immunotherapy.

Synergy between glutamate modulation and anti–programmed cell death protein 1 immunotherapy for glioblastoma

2021 ◽  
pp. 1-10
Author(s):  
Ravi Medikonda ◽  
John Choi ◽  
Ayush Pant ◽  
Laura Saleh ◽  
Denis Routkevitch ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Cell Death Protein

OBJECTIVE Immune checkpoint inhibitors such as anti–programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. METHODS C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. RESULTS The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). CONCLUSIONS In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

scholarly journals Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Ece Esin
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Small Subset ◽  
New Class ◽  
Combination Strategies ◽  
Combination Methods ◽  
Immune Editing ◽  
Cell Death Protein

In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the “checkpoint inhibitors.” Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years.

scholarly journals Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies

Blood ◽  
2016 ◽  
Vol 127 (26) ◽  
pp. 3350-3359 ◽  
Author(s):  
Chuang Sun ◽  
Gianpietro Dotti ◽  
Barbara Savoldo
Keyword(s):  
Tumor Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Hematologic Malignancies ◽  
Donor Lymphocyte Infusion ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Effector Cells

Abstract Hematologic malignancies provide a suitable testing environment for cell-based immunotherapies, which were pioneered by the development of allogeneic hematopoietic stem cell transplant. All types of cell-based therapies, from donor lymphocyte infusion to dendritic cell vaccines, and adoptive transfer of tumor-specific cytotoxic T cells and natural killer cells, have been clinically translated for hematologic malignancies. The recent success of chimeric antigen receptor–modified T lymphocytes in B-cell malignancies has stimulated the development of this approach toward other hematologic tumors. Similarly, the remarkable activity of checkpoint inhibitors as single agents has created enthusiasm for potential combinations with other cell-based immune therapies. However, tumor cells continuously develop various strategies to evade their immune-mediated elimination. Meanwhile, the recruitment of immunosuppressive cells and the release of inhibitory factors contribute to the development of a tumor microenvironment that hampers the initiation of effective immune responses or blocks the functions of immune effector cells. Understanding how tumor cells escape from immune attack and favor immunosuppression is essential for the improvement of immune cell–based therapies and the development of rational combination approaches.

scholarly journals Immune Thrombocytopenia Induced by Immune Checkpoint Inhibitrs in Lung Cancer: Case Report and Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Wang Xie ◽  
NaNa Hu ◽  
LeJie Cao
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Clinical Presentation ◽  
Checkpoint Inhibitors ◽  
Immune Dysregulation ◽  
Cancer Case ◽  
Severe Thrombocytopenia ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs), including antibodies targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1), are being extensively used on advanced human malignancies therapy. The treatment with ICIs have acquired durable tumor inhibition and changed the treatment landscape in lung cancer. Immune-related adverse events including pneumonitis and thyroiditis have been well described, but less frequent events, such as ICIs-induced thrombocytopenia, are now emerging and may sometimes be severe or fatal. Since early detection and prompt intervention are crucial to prevent fatal consequences, it is of outmost importance that medical staff is aware of these potential toxicities and learn to recognize and treat them adequately. This review focuses on the epidemiology, clinical presentation, mechanisms, and clinical management of ICIs-induced thrombocytopenia in patients with lung cancer. We also present a patient with advanced lung adenocarcinoma who received the PD-L1 inhibitor atezolizumab and eventually developed severe thrombocytopenia. The case indirectly suggests that cytokine changes might contribute to immune dysregulation in ICIs-induced thrombocytopenia.

scholarly journals Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

2021 ◽  
Vol 22 (16) ◽  
pp. 9030
Author(s):  
Justyna Błach ◽  
Kamila Wojas-Krawczyk ◽  
Marcin Nicoś ◽  
Paweł Krawczyk
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Resistance ◽  
Immune Checkpoints ◽  
Cytotoxic T Cell ◽  
Number Of Patients ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs) have a huge impact on clinical treatment results in non-small cell lung cancer (NSCLC). Blocking antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) or CTLA-4 (cytotoxic T cell antigen 4) have been developed and approved for the treatment of NSCLC patients. However, a large number of patients develop resistance to this type of treatment. Primary and secondary immunotherapy resistance are distinguished. No solid biomarkers are available that are appropriate to predict the unique sensitivity to immunotherapy. Knowledge of predictive markers involved in treatment resistance is fundamental for planning of new treatment combinations. Scientists focused research on the use of immunotherapy as an essential treatment in combination with other therapy strategies, which could increase cancer immunogenicity by generating tumor cells death and new antigen release as well as by targeting other immune checkpoints and tumor microenvironment. In the present review, we summarize the current knowledge of molecular bases underlying immunotherapy resistance and discuss the capabilities and the reason of different therapeutic combinations.

Autoimmune complications of immunotherapy: pathophysiology and management

BMJ ◽  
2020 ◽  
pp. m736 ◽  
Author(s):  
Karmela K Chan ◽  
Anne R Bass
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Case Fatality ◽  
High Grade ◽  
Almost All ◽  
Inhibitory Molecules ◽  
Patients Experience ◽  
Cell Death Protein

Abstract Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows.

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