scholarly journals Melanoma Cell State-Specific Responses to TNFα

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 605
Author(s):  
Su Yin Lim ◽  
Sara Alavi ◽  
Zizhen Ming ◽  
Elena Shklovskaya ◽  
Carina Fung ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
T Cell Activation ◽  
Melanoma Cell ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Melanoma Cells ◽  
Necrosis Factor Alpha ◽  
Hla Dr ◽  
Differentiation Status

Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD1) pathway have revolutionized the treatment of patients with advanced metastatic melanoma. PD1 inhibitors reinvigorate exhausted tumor-reactive T cells, thus restoring anti-tumor immunity. Tumor necrosis factor alpha (TNFα) is abundantly expressed as a consequence of T cell activation and can have pleiotropic effects on melanoma response and resistance to PD1 inhibitors. In this study, we examined the influence of TNFα on markers of melanoma dedifferentiation, antigen presentation and immune inhibition in a panel of 40 melanoma cell lines. We report that TNFα signaling is retained in all melanomas but the downstream impact of TNFα was dependent on the differentiation status of melanoma cells. We show that TNFα is a poor inducer of antigen presentation molecules HLA-ABC and HLA-DR but readily induces the PD-L2 immune checkpoint in melanoma cells. Our results suggest that TNFα promotes dynamic changes in melanoma cells that may favor immunotherapy resistance.

scholarly journals Biomarkers for non-small cell lung cancer immunotherapy

2021 ◽  
Vol 2 (3) ◽  
pp. 31-41
Author(s):  
D. A. Kharagezov ◽  
Yu. N. Lazutin ◽  
E. Yu. Zlatnik ◽  
A. B. Sagakyants ◽  
E. A. Mirzoyan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
T Cell Activation ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung

The discovery of immune checkpoint inhibition has revolutionized the treatment of many solid malignancies, including non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) can restore the antitumor immune response by blocking the inhibition of T-cell activation. Anti-programmed death-ligand 1 (PD-L1) is currently the main biomarker of the effectiveness of anti-PD-1 / PD-L1 blockade in the treatment of NSCLC without driver mutations. High tumor mutational burden suggests an increased neoantigens load and has been associated with the effectiveness of ICI therapy. Microsatellite instability, a biomarker approved for immunotherapy across solid tumors, but it is uncommon in NSCLC. Primary resistance to ICIsis characteristic of NSCLC with driver mutations, acquired is associated with immunoediting resulting in the depletion of potentially immunogenic neoantigens. The review discusses recent advances and future directions for predicting the results of immunotherapy in patients with NSCLC.

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.

Expression of Molecules Involved in Antigen Presentation and T Cell Activation (HLA-DR, CD80, CD86, CD44 and CD54) by Cultured Human Osteoblasts

2000 ◽  
Vol 71 (4) ◽  
pp. 614-617 ◽  
Author(s):  
C. Reyes-Botella ◽  
M.J. Montes ◽  
M.F. Vallecillo-Capilla ◽  
E.G. Olivares ◽  
C. Ruiz
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Osteoblasts ◽  
Hla Dr

scholarly journals Severe Gastritis after Administration of Nivolumab and Ipilimumab

2018 ◽  
Vol 11 (2) ◽  
pp. 549-556 ◽  
Author(s):  
Yoshito Nishimura ◽  
Miho Yasuda ◽  
Kazuki Ocho ◽  
Masaya Iwamuro ◽  
Osamu Yamasaki ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Metastatic Malignant Melanoma ◽  
Japanese Woman ◽  
H Pylori ◽  
Inhibitor Treatment

Immune checkpoint inhibitors such as ipilimumab, a cytotoxic T-lymphocyte-associated antigen-4 inhibitor, have been widely used for advanced malignancies. As these inhibitors improve antitumor immunity via T-cell modulation, immune-mediated adverse events associated with T-cell activation, such as colitis, might occur. Herein, we describe a 75-year-old Japanese woman with metastatic malignant melanoma who developed hemorrhagic gastritis after ipilimumab treatment. There was no macroscopic or clinical improvement of gastritis after proton pump inhibitor treatment. However, her condition improved after approximately 3 weeks of corticosteroid therapy and Helicobacter pylori eradication. This case suggests a potential association between severe gastritis and immune checkpoint inhibitor treatment. Although several reports have mentioned ipilimumab-associated colitis, gastritis is considered to be rare. In the present case, H. pylori-associated gastritis might have been exacerbated by the T-cell modulation effect of ipilimumab. To date, no report has clarified the mechanism by which ipilimumab modifies H. pylori infection. The present treatment course provides a helpful perspective for similar cases.

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 Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Selina K. Wong ◽  
Caroline A. Nebhan ◽  
Douglas B. Johnson
Keyword(s):  
Clinical Efficacy ◽  
T Cell Activation ◽  
Anticancer Agents ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Significant Heterogeneity ◽  
Older Individuals ◽  
Age Related

The addition of immune checkpoint inhibitors (ICIs) to the therapeutic armamentarium for solid malignancies has resulted in unprecedented improvements in patient outcomes in many cancers. The landscape of ICIs continues to evolve with novel approaches such as dual immune checkpoint blockade and combination therapies with other anticancer agents including cytotoxic chemotherapies and/or antiangiogenics. However, there is significant heterogeneity seen in antitumor responses, with certain patients deriving durable benefit, others experiencing initial benefit followed by acquired resistance necessitating change in therapy, and still others who are primarily refractory to ICIs. While generally better tolerated than traditional cytotoxic chemotherapy, ICIs are associated with unique toxicities, termed immune-related adverse events (irAEs), which can be severe or even lethal. As a disease of aging, older individuals make up a large proportion of patients diagnosed with cancer, yet this population is often underrepresented in clinical trials. Because ICIs indirectly target malignant cells through T cell activation, it has been hypothesized that age-related changes to the immune system may impact the efficacy and toxicity of these drugs. In this review, we discuss differences in the clinical efficacy and toxicity of ICIs in patients at the extremes of age.

Immune checkpoint inhibitors in the treatment of cancer

2021 ◽  
Vol 16 ◽  
Author(s):  
Wissam Zam ◽  
Lina Ali
Keyword(s):  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Research Field ◽  
Cell Lung Carcinoma ◽  
Checkpoint Proteins

Background: Immunotherapy drugs, known as immune checkpoint inhibitors (ICIs), work by blocking checkpoint proteins from binding with their partner proteins. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) that showed potent immune-modulatory effects through their function as negative regulators of T cell activation. Methods: In view of the rapid and extensive development of this research field, we conducted a comprehensive review of the literature and update on the use of CTLA-4, PD-1 and PD-L1 targeted therapy in the treatment of several types of cancer including melanoma, non-small-cell lung carcinoma, breast cancer, hepatocellular carcinoma, hodgkin lymphoma, cervical cancer, head and neck squamous cell carcinoma. Results: Based on the last updated list released on March 2019, seven ICIs are approved by the FDA including ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and cemiplimab. Conclusion: This review also highlighted the most common adverse effects caused by ICIs and which affect people in different ways.

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