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The new chapter in tumor immunotherapy—immunological checkpoint inhibitors

Because of its significant survival benefit, tumor immunotherapy has become a new effective treatment option for cancer followed by surgery, chemotherapy, radiotherapy and targeted therapy. As one of the methods for tumors, immunological checkpoint inhibitors have been approved for the treatment of a variety of advanced tumors. Although some cancer patients can benefit from it, the immune-related adverse reactions, primary drug resistance and secondary drug resistance during the clinical use of the inhibitor limit its wide clinical application. Biomarker studies related to the efficacy of immunological checkpoint inhibitors are helpful for the screening and individualized treatment of patients, and are of great significance for the regulation of immunosuppressive monotherapy or combination therapy.
With the deepening of basic research on tumor immunity, researchers found that the immune system can not only identify and eliminate tumor cells, but also help tumors escape immune attacks. Immune escape is one of the basic features of tumors. Tumors gradually acquire the ability of immune escape by their own genes, epigenetic changes and domestication of the surrounding environment. The ligand receptor binding at the immune checkpoint inhibits activated T lymphocytes, which is the key cause of immune escape. Therefore, researchers try to block the binding of ligand receptors at the immune checkpoint to activate immune cells and achieve anti-tumor effects, thus opening a new chapter in tumor immunotherapy.
Immunological checkpoint inhibitors have been approved for their use against advanced or metastatic melanoma, non-small cell lung cancer, kidney cancer, classic Hodgkin's lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, Merkel cell carcinoma and the treatment of solid tumors with high microsatellite instability or mismatch repair defects. Some of the representative inhibitors include cytolytic T lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor 1 (PD-1) and their ligand (PD-L1) antibodies.. However, there are two problems in clinical application:
a.25% to 30% of patients will develop immune-related adverse reactions, including skin reactions, colitis, endocrine diseases and liver damage, and the incidence of grade 3 to 4 adverse reactions account for 6% to 10%, more serious patients will lead to death;
b.60% to 80% of cancer patients appear indications of primary drug resistance, and clinical study follow-up results show that 30% of patients appear secondary drug resistance.
Biomarker research related to immunological checkpoint inhibitors can help us achieve patient screening and individualized treatment, avoid over-medication, reduce the occurrence of adverse reactions, and ultimately improve patients' quality of life and prolong patient survival. Therefore, it is particularly urgent and important to study and identify biomarkers related to the efficacy of immunological checkpoint inhibitors.
1.Mechanism of action of immunological checkpoint inhibitors
The immune checkpoint is a class of molecules that negatively regulate the immune response of the body in a physiological condition. It maintains the body's immune tolerance and reduces the damage of the tissue during the immune response. From the uptake, processing and presentation of tumor antigens to the activation, migration, infiltration and killing of T lymphocytes, each step of the tumor's immune cycle is regulated by immune checkpoints. One of the mechanisms by which tumors evade immune attacks is to down-regulate immune responses using immune checkpoints.
Taking two types of immunological checkpoint inhibitor approved by the US Food and Drug Administration (FDA) as example: a. CTLA-4 is expressed in T lymphocytes of the central lymphoid organ, which regulates the activation of T lymphocytes in the early stages of the tumor immune cycle. The signal of T lymphocyte activation is that the receptor on the surface of T lymphocytes specifically binds to the antigen; the co-stimulatory molecule can bind to the leukocyte differentiation antigen 28 (CD2(a) and present on the cell surface of the ligand leukocyte differentiation antigen 80/ 86 (CD80/CD86). CTLA-4 competitively binds to the ligand of its homologous analog, CD28, thereby negatively regulating the activation of T lymphocytes. B. The 2PD-1 molecule is mainly expressed on the surface of immune cells in peripheral tissues, especially in the tumor microenvironment. The PD-1 molecule on the surface of T lymphocytes binds to the PD-L1 molecule on the surface of tumor cells, which weakens the immune response signal and ultimately inhibits the killing of tumor cells by T lymphocytes. Therefore, anti-CTLA-4 antibody and anti-PD-1/PD-L1 antibody can effectively relieve the braking effect of the immune checkpoint on the anti-tumor immune response of T lymphocytes, thereby achieving the effect of treating tumor.
New immune checkpoint molecules such as indoleamine-2,3 plus dioxygenase (IDO), lymphocyte activating gene 3 (LAG3) and T cell membrane protein 3 (TIM-3) have also been found to be involved in tumor immune escape, The actual clinical efficacy of the inhibitors needs to be tested in the results of large-scale prospective clinical studies.
To be continued in Part Two…
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publié le mardi 13 août à 14:50

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