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Principles of systemic treatment
Published in Peter Hoskin, Peter Ostler, Clinical Oncology, 2020
In recent years, a number of drugs targeting the immune response provoked by tumour antigens have been developed. Tumour antigens binding to the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death (PD)-1 binding sites on a CD8 T cell will result in the downregulation of the immune response to the tumour antigen enabling tumour growth. Immunomodulating drugs target PD-1 receptor and its ligands PD-L1 and PD-L2 or the CTLA-4 receptor by blocking this action of tumour antigens and enhancing the immune response.
Cell-mediated immunity
Published in Gabriel Virella, Medical Immunology, 2019
José C. Crispín, Gabriel Virella
Programmed death-1 (PD-1) is another coinhibitory molecule that is upregulated on T cells following activation. It has two known ligands, PD-L1 and PD-L2. Whereas expression of PD-L2 is largely confined to APCs, PD-L1 is also present on the surface of nonimmune cells. Signaling through PD-1 maintains immune tolerance, as its deficiency or blockade unleashes autoimmune phenomena. In some instances, for example in cancer and chronic viral infections, PD-1 signaling inhibits potentially beneficial T-cell effector responses, and its blockade has been used therapeutically to reinvigorate the cellular immune response.
Targeted Therapies
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
The PD-1 receptor together with its two ligands (PD-L1 and PD-L2) play a significant role in T-cell regulation to such extent that the inhibition of the PD-1 protein can activate T cells that trigger immune responses against malignant cells. Of particular importance is the PD-1/PD-L1 pathway that regulates T cell activity during inflammatory response to infection. PD-L1 is expressed by several cancers, including squamous cell carcinomas of the head and neck. This information is important since cancer cells that express PD-L1 were shown to evade the host immune system, while inhibition of PD-1 enhances tumour response to treatment (Müller et al. 2017).
The dual checkpoint blockade in unresectable hepatocellular carcinoma: opportunities emerging in clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Antonella Cammarota, Valentina Zanuso, Antonio D’Alessio, Tiziana Pressiani, Silvia Bozzarelli, Nicola Personeni, Lorenza Rimassa
Nivolumab is a human immunoglobulin G4 (IgG4) mAb targeting the immune checkpoint PD-1 [32]. PD-L1 and PD-L2 bind to the PD-1 receptor on T-cells, inhibiting T-cell proliferation and cytokine production. Nivolumab binds to PD-1, restoring tumor-specific T-cell response, finally resulting in reactivation of the immune system [33]. Nivolumab has a long duration of action and is administered intravenously (IV) at a dose of 240 mg every two, 360 mg every three, or 480 mg every four weeks. It presents linear pharmacokinetics with a time to peak plasma concentration between 1 and 4 hours, while its half-life after a single dose is estimated between 12 days (for 0.3, 1, or 3 mg/kg dose levels) and 20 days (for 10 mg/kg dose level). As a human mAb, it is degraded to small peptides and individual amino acids [32].
PD-L1 and PD-L2 Mutations in Pediatric Hodgkin Lymphoma: Do They Have Any Prognostic Significance?
Published in Fetal and Pediatric Pathology, 2022
Gülen Gül, Dilek Ince, Nur Olgun, Erdener Ozer
PD-1 protein is one of the most important immune control proteins and expressed by receptor-activated T cells. PD-1 mediates immunosuppression and has two ligands known as PD-L1 (B7-H1) and PD-L2 B7-DC [5]. PD-L1 and PD-L2 proteins are signal molecules expressed on surfaces of the antigen presenting cells. When they interact with the receptor PD-1 on effector T cells, they send a negative regulatory signal that leads to the functional anergy of T cells [15]. The physiological role of PD-1 is to ensure T cell homeostasis and the balance between T cell activation and proliferation. Binding of PD-L1 and PD-L2 to PD-1 gives an inhibitory signal and reduces cytokine production and proliferation of the activated T cells allowing the tumor cells to escape from immune control [6,7]. This immune checkpoint is very important for both tumor progression and treatment. Therefore, we think that the immune response in HL is likely to be influenced by the PD-1 signaling pathway.
PD-L2 based immune signature confers poor prognosis in HNSCC
Published in OncoImmunology, 2021
Yu Qiao, Chao Liu, Xiaoyue Zhang, Qianqian Zhou, Yatian Li, Yini Xu, Zhenyue Gao, Yiqi Xu, Lingping Kong, Aifeng Yang, Mei Mei, Yu Ren, Xudong Wang, Xuan Zhou
PD-L2 is another ligand of PD-1, which is similar to PD-L1 in some functions and mainly affects the regulatory T cells.20 PD-L2 is reported to be important for the response of patients who are PD-L1-negative to PD-1 inhibitors.21 The PD-1 binding affinity of PD-L2 is approximately 2-6-fold higher compared to PD-L1.22 PD-L2 was originally found to be expressed in dendritic and macrophages cells.23 However, recent studies demonstrated that PD-L2 is overexpressed in many solid malignancies, including HNSCC,21,24 suggesting that abnormal intratumoural PD-L2 expression promotes immunosuppression. In certain cancers including colorectal, esophageal, pancreatic and renal cell carcinomas, PD-L2 expression has been reported as an independent marker for poor outcomes.24–27 High PD-L2 expression on PD-1+ tumor infiltrating lymphocytes (TILs) was detected, suggesting its immunosuppressive role.28,29 PD-L2 expression was detected in HNSCC and prostate cancer, which are typically PD-L1-negative.21,30 These studies indicated that intratumoural PD-L2 level may serve as a predictive marker or target for anti-PD-1 therapy response evaluation in HNSCC.