Overview of Costimulatory Genes
The immune system is an important line of defense for the human body to resist foreign invasion and clear internal abnormalities. It is composed of a variety of immune cells and molecules, and maintains the immune balance of the body through complex signal transduction and regulatory mechanisms. However, when the immune system is disturbed or unbalanced, it will lead to various immune-related diseases, such as cancer, autoimmune diseases, infectious diseases and so on. Therefore, how to effectively regulate the function of the immune system and improve the body's immune response and tolerance is one of the major challenges facing the medical community. Immunotherapy is a treatment method that uses the body's own immune system to identify and eliminate abnormal cells or microorganisms. It has the advantages of high specificity, persistence and memory, and has become one of the effective means for the treatment of various immune-related diseases. one. However, immunotherapy also has some limitations and problems, such as immune escape, side effects, drug resistance, etc., which affect the efficacy and safety of immunotherapy. Therefore, finding new immunotherapy targets and strategies to improve the efficiency and accuracy of immunotherapy is an important topic in the field of immunotherapy.
Costimulatory genes refer to genes encoding costimulatory molecules or their receptors involved in T cell activation and enhancement. Costimulatory molecules are a class of membrane-bound proteins expressed on antigen-presenting cells (APCs) or T cells, which provide a second signal to T cells by binding to corresponding ligands or receptors, thereby regulating the proliferation of T cells, differentiation, polarization and function. Costimulatory molecules mainly include B7-CD28 family and tumor necrosis factor (TNF) family. Different costimulatory molecules have different effects on T cells, some are positive costimulatory molecules that promote T cell activation and enhancement, such as CD28, CD40, OX40; some are negative costimulatory molecules that inhibit T cell activation and enhancement, such as CTLA4, PD-1, TIM-3. Costimulatory genes play a key role in regulating the body's immune balance and immune response, and their expression and function are also different in different types of immune-related diseases. In recent years, with the in-depth revelation of the mechanism of action of costimulatory genes in immunology, they have become one of the most promising and potential targets in the field of immunotherapy.
Expression and Regulation of Costimulatory Genes in Different Types of Diseases
Costimulatory genes refer to a class of genes that can regulate the activation and function of T cells. They mainly encode costimulatory molecules or their receptors, such as CD28, CTLA4, ICOS, and PD1. Costimulatory genes play an important role in the immune system because they can affect T cell antigen recognition, proliferation, differentiation and memory. The expression and regulation of costimulatory genes are affected by many factors, including the intensity of antigen stimulation, cell type, differentiation state, signaling pathways, transcription factors, and epigenetic modifications. Costimulatory genes also have different manifestations and roles in different types of diseases, such as cancer, autoimmune diseases, infectious diseases, etc.
In cancer, costimulatory genes are often downregulated or inactivated, leading to T cell hypofunction or tolerance, thereby allowing tumor cells to escape immune surveillance and clearance. For example, CTLA4 is a negative regulatory molecule that can compete with CD28 for binding to B7 molecules and inhibit T cell activation. CTLA4 is highly expressed in tumor-infiltrating T cells (TILs) and reduces the response of TILs to tumor antigens. PD1 is another negative regulatory molecule that can bind to PD-L1 or PD-L2 to inhibit T cell proliferation and effector function. PD1 is also highly expressed in TILs, and tumor cells are often able to resist immune attack by upregulating PD-L1 or PD-L2. On the contrary, some positive regulatory molecules, such as CD28, ICOS, are under-expressed or absent in TILs, leading to insufficient activation or senescence of T cells.
In autoimmune diseases, costimulatory genes are usually up-regulated or over-activated, leading to hyperfunction or loss of control of T cells, thereby causing immune damage to self-organized tissues. For example, in rheumatoid arthritis (RA), CD28 is highly expressed on CD4+ T cells, enhancing T cell responses to self-antigens. CTLA4 is under-expressed or functionally defective in peripheral blood mononuclear cells (PBMCs) of RA patients, reducing negative feedback regulation of T cells. ICOS is highly expressed in the synovial tissue of RA patients, which promotes the differentiation of Th17 cells and the production of IL-17. PD1 is also highly expressed in PBMCs of RA patients, but PD-1 signaling pathway is disrupted or counteracted, leading to T cell escape from apoptosis.
In infectious diseases, costimulatory genes often vary according to the type and stage of infection to accommodate the needs of the immune response. For example, in tuberculosis infection, CD28 is upregulated at an early stage to promote Th1 cell differentiation and IFN-γ production. CTLA4 is upregulated at later stages to limit overactivated Th1 cells and TNF-α production. PD1 is upregulated during persistent infection to induce T cell tolerance and apoptosis. ICOS is also upregulated in tuberculosis infection, but its role is unclear.
In conclusion, costimulatory genes have different expression and regulatory patterns in different types of diseases, reflecting their important roles in immune balance and homeostasis. There are also interactions and synergies between different costimulatory genes, forming a complex network system. Understanding the mechanism and influencing factors of costimulatory genes in different types of diseases will help to develop more effective and safe immunotherapy methods.
Application and Progress of Costimulatory Genes in Immunotherapy
The application of costimulatory genes in immunotherapy mainly uses costimulatory molecules or their receptors as targets, or uses methods such as costimulatory gene transfection or knockout to change the function of immune cells to enhance or inhibit the activation and effect of T cells, thereby achieve the purpose of treatment. At present, a variety of immunotherapy strategies based on costimulatory genes have achieved certain results in clinical trials, such as anti-CTLA4, anti-PD1, anti-PD-L1 and other monoclonal antibodies, as well as CAR-T cells, TCR-T cells, etc. Genetically engineered cells.
Anti-CTLA4 monoclonal antibody is an immune checkpoint inhibitor that can block the binding of CTLA4 to B7 molecules, thereby releasing the CD28 signaling pathway and enhancing T cell activation and proliferation. Currently, two anti-CTLA4 monoclonal antibodies have been approved by for the treatment of advanced melanoma, namely ipilimumab and tremelimumab. Anti-CTLA4 monoclonal antibody can significantly improve the survival time and cure rate of melanoma patients, but it is also accompanied by high toxicity and side effects, such as autoimmune hepatitis, colitis, dermatitis, etc. Therefore, how to reduce the toxicity and side effects of anti-CTLA4 monoclonal antibodies, and how to improve their effectiveness against other types of cancers are urgent problems to be solved.
Anti-PD1 and anti-PD-L1 monoclonal antibodies are another immune checkpoint inhibitor that can block the binding of PD1 to PD-L1 or PD-L2, thereby restoring T cell function. At present, a variety of anti-PD1 and anti-PD-L1 monoclonal antibodies have been approved for the treatment of various types of cancer, such as non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, etc. Anti-PD1 and anti-PD-L1 monoclonal antibodies have broader indications and lower toxicity and side effects than anti-CTLA4 monoclonal antibodies. However, not all patients benefit from these drugs, and some patients have primary or acquired drug resistance. Therefore, there is a need to find ways to predict and improve patient response rates to these drugs, as well as to overcome resistance mechanisms.
CAR-T cells are a kind of artificially synthesized chimeric antigen receptor (CAR) containing CD3ζ chain and costimulatory domain (such as CD28, CD137, ICOS, etc.) A cell therapy method in which cells can recognize and kill tumor cells expressing specific targets (such as CD19, CD20, etc.). Currently, two CAR-T cells targeting the CD19 target have been approved for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and large B-cell lymphoma (DLBCL), tisagenlecleucel and axicabtagene ciloleucel. CAR-T cells can produce durable and powerful tumor killing effects, but there are also serious toxicity and side effects, such as cytokine release syndrome (CRS), neurotoxicity, B cell deficiency, etc. In addition, the effectiveness of CAR-T cells against solid tumors needs to be improved. Therefore, it is necessary to optimize the design and preparation of CAR-T cells, as well as reduce their toxicity and side effects.
TCR-T cells are a cell therapy method that uses genetic engineering technology to transfect specific T cell receptors (TCR) onto T cells, so that T cells can recognize and kill tumor cells expressed by specific peptide-MHC complexes. TCR-T cells have a wider range of target selection than CAR-T cells because they can recognize tumor endogenous antigens or neoantigens. At present, a TCR-T cell targeting NY-ESO-1 has been approved to enter the clinical trial stage. TCR-T cells have shown certain effects in clinical trials, but there are still some problems, such as TCR mismatch, HLA restriction, tumor escape and so on. Therefore, it is necessary to solve the problem of how to improve the specificity and safety of TCR-T cells, and how to expand the scope of its indications.
Taken together, costimulatory genes have important application value and development potential in immunotherapy. Immunotherapy strategies based on costimulatory genes can effectively regulate T cell function and have achieved remarkable results in various types of cancer. However, there are also some limitations and problems in practical applications, such as toxicity, side effects, drug resistance, etc. Therefore, in the future, it is necessary to further explore the mechanism and influencing factors of costimulatory genes in different types of cancer, and develop new costimulatory molecules or receptors, new drugs or carriers, and new combination therapy to improve the effect of immunotherapy.
Performance and Prospects of Costimulatory Genes in Clinical Trials
The performance of costimulatory genes in clinical trials is mainly to evaluate the safety and effectiveness of costimulatory gene-based immunotherapy strategies for patients with different types of cancer, as well as the comparison and combination with other treatment methods. At present, a number of clinical trials have explored and verified different costimulatory molecules or their receptors, such as CTLA4, PD1, PD-L1, CD28, CD137, ICOS, etc.
The performance of CAR-T cells in clinical trials was mainly evaluated for patients with hematologic malignancies. One of the earliest clinical trials, in 2017, evaluated tisagenlecleucel in patients with relapsed or refractory B-ALL. The results showed that tisagenlecleucel was able to induce complete remission in 83% of patients and had a long-term survival rate. A follow-up clinical trial was carried out in 2018, which evaluated the treatment effect of axicabtagene ciloleucel in patients with relapsed or refractory DLBCL. The results showed that axicabtagene ciloleucel was able to induce complete remission in 52% of patients and a long-term survival rate. However, the effectiveness of CAR-T cells in solid tumors remains to be improved. For example, in gastric cancer, CAR-T cells targeting HER2 can only induce some patients to reach a stable state, accompanied by high toxicity and side effects.
The performance of TCR-T cells in clinical trials was mainly evaluated for patients with solid tumors. The earliest clinical trial was in 2017, evaluating the effect of TCR-T cells targeting NY-ESO-1 on patients with advanced solid tumors (such as melanoma, ovarian cancer, lung cancer). The results showed that TCR-T cells were able to induce objective responses in 61% of patients and had a long-term survival rate. A follow-up clinical trial was conducted in 2019, evaluating the effect of TCR-T cells targeting MAGE-A4 on patients with advanced solid tumors (such as esophageal cancer, gastric cancer, lung cancer). The results showed that TCR-T cells were able to induce objective responses in 25% of patients and had a long-term survival rate.
