scholarly journals B7 Family Members in Lymphoma: Promising Novel Targets for Tumor Immunotherapy?

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Zhang ◽  
Yu Qiu ◽  
Xiaoli Xie ◽  
Yao Fu ◽  
Lijuan Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Vital Role ◽  
Immune Checkpoints ◽  
Programmed Death ◽  
B7 Family ◽  
Cell Death Protein

T cells play a vital role in the immune responses against tumors. Costimulatory or coinhibitory molecules regulate T cell activation. Immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have shown remarkable benefits in patients with various tumor, but few patients have displayed significant immune responses against tumors after PD-1/PD-L1 immunotherapy and many have been completely unresponsive. Thus, researchers must explore novel immune checkpoints that trigger durable antitumor responses and improve clinical outcomes. In this regard, other B7 family checkpoint molecules have been identified, namely PD-L2, B7-H2, B7-H3, B7-H4 and B7-H6. The aim of the present article was to address the expression, clinical significance and roles of B7 family molecules in lymphoma, as well as in T and NK cell-mediated tumor immunity. B7 family checkpoints may offer novel and immunotherapeutic strategies for patients with lymphoma.

scholarly journals Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies

2019 ◽  
Vol 8 (6) ◽  
pp. 762 ◽  
Author(s):  
Ryo Sato ◽  
Kosuke Imamura ◽  
Shinya Sakata ◽  
Tokunori Ikeda ◽  
Yuko Horio ◽  
...  
Keyword(s):  
Cancer Patients ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Early Period ◽  
University Hospital ◽  
Immune Checkpoints ◽  
Lung Cancer Patients

A disruption of immune checkpoints leads to imbalances in immune homeostasis, resulting in immune-related adverse events. Recent case studies have suggested the association between immune checkpoint inhibitors (ICIs) and the disorders of the coagulation-fibrinolysis system, implying that systemic immune activation may impact a balance between clotting and bleeding. However, little is known about the association of coagulation-fibrinolysis system disorder with the efficacy of ICIs. We retrospectively evaluated 83 lung cancer patients who received ICI at Kumamoto University Hospital. The association between clinical outcome and diseases associated with disorders of the coagulation-fibrinolysis system was assessed along with tumor PD-L1 expression. Among 83 NSCLC patients, total 10 patients (12%) developed diseases associated with the disorder of coagulation-fibrinolysis system. We found that disorders of the coagulation-fibrinolysis system occurred in patients with high PD-L1 expression and in the early period of ICI initiation. In addition, high tumor responses (72%) were observed, including two complete responses among these patients. Furthermore, we demonstrate T-cell activation strongly induces production of a primary initiator of coagulation, tissue factor in peripheral PD-L1high monocytes, in vitro. This study suggests a previously unrecognized pivotal role for immune activation in triggering disorders of the coagulation-fibrinolysis system in cancer patients during treatment with ICI.

scholarly journals Checkpoint Inhibitors in Breast Cancer - Current Status and Future Directions

Breast Care ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Joachim Bischoff
Keyword(s):  
Breast Cancer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Death Receptor ◽  
Target Population ◽  
Current Status ◽  
Immune Checkpoints ◽  
Breast Cancer Patients

Antineoplastic agents directly targeting tumor cells have represented the major strategy of systemic anticancer therapy for many years. Nevertheless, overcoming resistance mechanisms remains a great challenge because treatment options are limited in many cases. From this point of view, immunotherapeutic approaches seem promising in a broad spectrum of solid tumors. These include in particular the currently available inhibitors directed against immune checkpoints leading to a significant T-cell activation. To date, the programmed death receptor 1 (PD-1) and its ligand are the most prominent targets in this context. However, the role of checkpoint inhibitors in the treatment of breast cancer is still being debated, and the main focus is on triple-negative breast cancer patients as a target population in many ongoing trials. Moreover, the potential superiority of combinations with other anticancer drugs such as cytotoxics and targeted agents will be discussed.

scholarly journals AP-1 Transcription Factors as Regulators of Immune Responses in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1037 ◽  
Author(s):  
Vasileios Atsaves ◽  
Vasiliki Leventaki ◽  
George Z. Rassidakis ◽  
Francois X. Claret
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Success ◽  
Nuclear Gene ◽  
Mapk Signaling ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Activator Protein 1 ◽  
Oncogenic Signaling

Immune check point blockade therapy has revolutionized the standard of cancer treatment and is credited with producing remarkable tumor remissions and increase in overall survival. This unprecedented clinical success however is feasible for a limited number of cancer patients due to resistance occurring before or during a course of immunotherapy, which is often associated with activation of oncogenic signaling pathways, co-inhibitory checkpoints upregulation or expansion of immunosuppressive regulatory T-cells (Tregs) in the tumor microenviroment (TME). Targeted therapy aiming to inactivate a signaling pathway such as the Mitogen Activated Protein Kinases (MAPKs) has recently received a lot of attention due to emerging data from preclinical studies indicating synergy with immune checkpoint blockade therapy. The dimeric transcription factor complex Activator Protein-1 (AP-1) is a group of proteins involved in a wide array of cell processes and a critical regulator of nuclear gene expression during T-cell activation. It is also one of the downstream targets of the MAPK signaling cascade. In this review, we will attempt to unravel the roles of AP-1 in the regulation of anti-tumor immune responses, with a focus on the regulation of immune checkpoints and Tregs, seeking to extract useful insights for more efficacious immunotherapy.

scholarly journals Immune Evasion Mechanism and AXL

2021 ◽  
Vol 11 ◽  
Author(s):  
Hye-Youn Son ◽  
Hwan-Kyu Jeong
Keyword(s):  
Tumor Microenvironment ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Immune Evasion ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
Multiple Cancer ◽  
Clinical Prognosis ◽  
Programmed Death

Extensive interest in cancer immunotherapy is reported according to the clinical importance of CTLA-4 and (PD-1/PD-L1) [programmed death (PD) and programmed death-ligand (PD-L1)] in immune checkpoint therapies. AXL is a receptor tyrosine kinase expressed in different types of cancer and in relation to resistance against various anticancer therapeutics due to poor clinical prognosis. AXL and its ligand, i.e., growth arrest-specific 6 (GAS6) proteins, are expressed on many cancer cells, and the GAS6/AXL pathway is reported to promote cancer cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. AXL is an attractive and novel therapeutic target for impairing tumor progression from immune cell contracts in the tumor microenvironment. The GAS6/AXL pathway is also of interest immunologically because it targets fewer antitumor immune responses. In effect, several targeted therapies are selective and nonselective for AXL, which are in preclinical and clinical development in multiple cancer types. Therefore, this review focuses on the role of the GAS6/AXL signaling pathway in triggering the immunosuppressive tumor microenvironment as immune evasion. This includes regulating its composition and activating T-cell exclusion with the immune-suppressive activity of regulatory T cells, which is related to one of the hallmarks of cancer survival. Finally, this article discusses the GAS6/AXL signaling pathway in the context of several immune responses such as NK cell activation, apoptosis, and tumor-specific immunity, especially PD-1/PDL-1 signaling.

Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses

Science ◽  
2019 ◽  
Vol 364 (6440) ◽  
pp. 558-566 ◽  
Author(s):  
Daisuke Sugiura ◽  
Takumi Maruhashi ◽  
Il-mi Okazaki ◽  
Kenji Shimizu ◽  
Takeo K. Maeda ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
T Cell Responses ◽  
Cell Responses ◽  
Critical Components ◽  
Antigen Presenting ◽  
In Cis

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.

scholarly journals Immunotherapy in hematologic malignancies

2019 ◽  
Vol 27 (S2) ◽  
Author(s):  
R.R. Kansara ◽  
C. Speziali
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Hematologic Malignancies ◽  
Immune Checkpoints ◽  
Hematologic Neoplasms

The management of hematologic malignancies has traditionally relied on chemotherapy regimens, many of which are still in use today. However, with advancements in the knowledge of tumour pathophysiology, therapies are continually evolving. Monoclonal antibodies against specific targets on tumour cells are now widely used to treat hematologic malignancies, either in combination with chemotherapy or as single agents. Rituximab, a monoclonal antibody against the CD20 antigen, is a good example of successful monoclonal antibody therapy that has improved outcomes for patients with B cell non-Hodgkin lymphomas. Monoclonal antibodies are now being used against the immune checkpoints that function to inhibit T cell activation and subsequent tumour eradication by those cytotoxic T cells. Such therapies enhance T cell–mediated tumour eradication and are widely successful in treating patients with solid tumours such as malignant melanoma. Now, they are slowly finding their place in the management of hematologic neoplasms. Even though, currently, immune checkpoint inhibitors are used for relapsed or refractory hematologic neoplasms, trials are ongoing to evaluate their role in frontline treatment. Our review focuses on the current use of immunotherapies in various hematologic malignancies.

scholarly journals Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

Cell Research ◽  
2020 ◽  
Vol 30 (11) ◽  
pp. 966-979 ◽  
Author(s):  
Mengze Lv ◽  
Meixia Chen ◽  
Rui Zhang ◽  
Wen Zhang ◽  
Chenguang Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Cancer Therapeutics ◽  
Type I

Abstract CD8+ T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8+ T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8+ T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8+ T cells. Mechanically, Mn2+ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8+ T cell differentiation, activation and NK cell activation, and increased memory CD8+ T cells. Combining Mn2+ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn2+ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.

scholarly journals Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shuang Qin ◽  
Linping Xu ◽  
Ming Yi ◽  
Shengnan Yu ◽  
Kongming Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Immune Checkpoint Molecules

Abstract The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

scholarly journals Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Lilia Bardoscia ◽  
Nadia Pasinetti ◽  
Luca Triggiani ◽  
Salvatore Cozzi ◽  
Angela Sardaro
Keyword(s):  
Adverse Events ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Essential Components ◽  
Radiation Induced ◽  
Synergistic Modulation ◽  
Poor Outcomes ◽  
Effects Of Radiation

Immune checkpoint inhibitors have gained an established role in the treatment of different tumors. Indeed, their use has dramatically changed the landscape of cancer care, especially for tumor types traditionally known to have poor outcomes. However, stimulating anticancer immune responses may also elicit an unusual pattern of immune-related adverse events (irAEs), different from those of conventional chemotherapy, likely due to a self-tolerance impairment featuring the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction. Ionizing radiation has proven to promote both positive pro-inflammatory and immunostimolatory activities, and negative anti-inflammatory and immunosuppressive mechanisms, as a result of cross-linked interactions among radiation dose, the tumor microenvironment and the host genetic predisposition. Several publications argue in favor of combining immunotherapy and a broad range of radiation schedules, based on the recent evidence of superior treatment responses and patient survival. The synergistic modulation of the immune response by radiation therapy and immunotherapeutics, particularly those manipulating T-cell activation, may also affect the type and severity of irAEs, suggesting a relationship between the positive antitumor and adverse autoimmune effects of these agents. As yet, information on factors that may help to predict immune toxicity is still lacking. The aim of our work is to provide an overview of the biological mechanisms underlying irAEs and possible crosslinks with radiation-induced anticancer immune responses. We believe such an overview may support the optimization of immunotherapy and radiotherapy as essential components of multimodal anticancer therapeutic approaches. Challenges in translating these to clinical practice are discussed.

scholarly journals LAG-3: from molecular functions to clinical applications

2020 ◽  
Vol 8 (2) ◽  
pp. e001014
Author(s):  
Takumi Maruhashi ◽  
Daisuke Sugiura ◽  
Il-mi Okazaki ◽  
Taku Okazaki
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Drug Targets ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Transmembrane Protein ◽  
Lymphocyte Activation ◽  
Type I ◽  
Cancer Types

To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at multiple points. Inhibitory coreceptors, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against self-tissues and tumor cells. Immune checkpoint inhibitors that block PD-1 and CTLA-4 pathways significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment. However, response rates to such therapies are rather limited, and immune-related adverse events are also observed in a substantial patient population, leading to the urgent need for novel therapeutics with higher efficacy and lower toxicity. In addition to PD-1 and CTLA-4, a variety of stimulatory and inhibitory coreceptors are involved in the regulation of T cell activation. Such coreceptors are listed as potential drug targets, and the competition to develop novel immunotherapies targeting these coreceptors has been very fierce. Among such coreceptors, lymphocyte activation gene-3 (LAG-3) is expected as the foremost target next to PD-1 in the development of cancer therapy, and multiple clinical trials testing the efficacy of LAG-3-targeted therapy are underway. LAG-3 is a type I transmembrane protein with structural similarities to CD4. Accumulating evidence indicates that LAG-3 is an inhibitory coreceptor and plays pivotal roles in autoimmunity, tumor immunity, and anti-infection immunity. In this review, we summarize the current understanding of LAG-3, ranging from its discovery to clinical application.

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