Introduction of Immune Checkpoint
In tumor, cells will get many new characters from common cells to cancer cells. Compare with common cells, the feature of genetics and epigenetics has changed in cancer cells. The immune system can recognize cancerous cells and induce the immune response of anti-tumor. Therefore, the balance can be kept when a few cells are canceration. But immune suppression related with tumor blocks the effective immune response. T cells play a critical role in the process of effective immune response of anti-tumor. Due to the importance of T cells in the immune response, when T cells are activated by antigen recognition signals, various co-activation signals and co-suppression signals are used to finely adjust the intensity and quality of T cell responses. These inhibition signals are immune checkpoint. The significance of immune checkpoint is to participate in maintaining immune tolerance to autoantigens, avoiding autoimmune diseases, and avoiding damage to tissues caused by excessive activation of immune responses. In cancerous tissues, tumor cells can use immune checkpoints to inhibit T cell activation and thus evade immune killing. This is a key point in tumorigenesis in vivo. Therefore, enhancing the activation of T cells through different strategies is of great significance for tumor immunotherapy. The blocking of immune checkpoints is one of the effective strategies for enhancing T cell activation. The most in-depth studies about immune checkpoints currently include cytotoxic T lymphocyte antigen 4(CTLA-4), programmed death protein 1 and its ligands(PD-1/PDL-1), and its targeted inhibitors have entered clinical trials, and the US Food and Drug Safety Commission have also approved the first-generation immune checkpoint inhibitor ipilizumab (a monoclonal antibody that blocks CTLA-4). It is used to induce a sustained anti-tumor response to treat melanoma. At the same time, drugs that inhibit the checkpoint PD1 and its ligand PDL-1 have shown good therapeutic effects in many tumor treatments. In addition to the classic checkpoints CTLA-4 and PD-1/PDL-1, many new checkpoints have been discovered in recent years as potential immune targets, such as 4-1BB, OX40, CD27, LAG3, CD224, TN-FRSF25. Etc., drugs against these checkpoints block the transmission of inhibitory signals and induce antitumor effects of T cells.
The Regulation of T Cell Activation
Inducing an effective anti-tumor immune response is a multi-step complex process, and the key is that effector T cells can effectively recognize and kill tumor cells. The activation of T cells is a prerequisite for its anti-tumor effect. Tumor cells can use immune checkpoints to inhibit the activation of T cells, thereby evading the killing of the immune system.
The classical dual signal activation theory believes that the activation of T cells requires 2 kinds of signal. The first signal is specifically transmitted by the interaction between MHC-Ag complex on the surface of antigen-presenting cells (APCs) and TCR. The second signal is the binding of the expressed costimulatory molecule in APCs to the corresponding receptor of T cells. The most important of these is the binding of CD28 to B7.1 (CD80) on the surface of T cells. If the second signal is absent, it will cause T cell inactivation or apoptosis. CTLA-4 is an important inhibitory molecule expressed on the surface of activated T cells. It is homologous to CD28 and contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in the intracellular domain. After binding of B7.1 or B7.2, the ITIM motif can recruit phosphatase of the SHP family, which reverses the phosphorylation of signaling molecules caused by TCR activation, thereby inhibiting T cell activation. PD-1 is another important inhibitory receptor on the surface of T cells, homologous to CD28 and CTLA-4, and is named for its initial discovery in apoptotic T-cell lymphoma and its ability to promote programmed cell death. It is inducible expression in activated T cells, B cells, macrophages, dendritic cells, and monocytes, and is not expressed on the surface of resting lymphocytes. Upregulation of PD-1 expression on the surface of these activated lymphocytes can lead to inhibition of acquired or innate immune responses. The intracellular domain of PD-1 contains an ITIM motif and an immunoreceptor tyrosine-based switch motif (ITSM). The ITSM motif mediates the recruitment of SHP family phosphatases and inhibition of T cell activation signals. Binding of PD-1/PD-L1 plays an important role in regulating T cell activation and maintaining peripheral immune tolerance. However, tumor cells can inhibit the activation of T cells by expressing PD-L1 and interacting with PD-1 to escape the killing of immune cells. In addition, important co-suppressor receptors on the surface of T cells include B and T lymphocyte attenuator (BTLA), lymphocyte activation gene 3 (LAG3), CD160 and PD-1 homologous molecules (PD-1H) and the like.
Trends and Prospects
Unlike traditional cancer treatment methods, cellular immunotherapy aims to kill tumors by eliciting a specific and effective anti-tumor immune response. Blocking of immune checkpoints is an effective strategy to relieve the inhibition of T cell activation. In clinical trial, monoclonal antibodies targeting CTLA-4 and PD-1/PD-L1 achieve definite therapeutic effects, and these drugs have appeared on the market. However, due to the limitations of the clinical application of immunological checkpoint drugs, the treatment of tumor immune checkpoints needs to be more precise and individualized. The use of high-throughput sequencing screens to identify specific mutations in cancer cells in specific patients, and to choose appropriate anti-tumor immunotherapies for patients. This will be a trend and requirement for anti-tumor immunotherapy in the future. Improving the understanding of tumor immune response regulation, patient selectivity, and biological targets will help improving the immunotherapeutic effect of cancer patients. Considering the diversity of immunosuppressive mechanisms, the development of combination therapy will be a key point in strengthening cancer immunotherapy, and it is an effective means of future cancer treatment.