Overview of Tumor-Associated Antigen Genes

Tumor immunotherapy is a therapeutic strategy that uses the body's own immune system to identify and eliminate tumor cells, and has achieved remarkable clinical results in recent years. Among them, immune checkpoint inhibitors activate tumor-specific T cells by releasing the inhibitory signal during T cell activation, thereby achieving anti-tumor effects. However, immune checkpoint inhibitors are only effective for some patients, and there are problems such as drug resistance and side effects. These issues are closely related to the quality and quantity of tumor antigens. Tumor antigens refer to peptides presented by human leukocyte antigen (HLA) that can be recognized by T cell receptors and cause immune responses. They can be divided into various types according to their origin and characteristics, such as tumor-specific antigens, tumor-associated antigens, and atypical antigens. Among them, tumor-associated antigen genes are a class of genes encoding tumor-associated antigens (TAAs), which are only expressed in germ cells in normal tissues, and are abnormally activated and expressed in various malignant tumors. TAAs are highly immunogenic and tissue-specific, making them ideal targets for tumor immunotherapy.

Regulatory Mechanism of TAA Expression in Tumor Cells

TAAs are a class of genes encoding tumor-associated antigens, which are only expressed in germ cells in normal tissues and are abnormally activated and expressed in various malignant tumors. Most of the TAAs are located on the X chromosome, forming a multi-gene family with a high degree of homology and conservation. The gene structure and expression pattern of TAAs are similar to those in normal germ cells, but there are some differences, such as splicing variation, promoter variation, and polymorphism. The expression of TAAs is regulated at multiple levels, including transcription, splicing, translation, degradation, and antigen presentation. At the transcriptional level, DNA methylation and histone modification are the main factors affecting the expression of TAAs. They regulate the binding of transcription factors in the promoter regions of TAA genes by changing the chromatin structure and accessibility. In addition, some microRNAs (miRNAs) and long non-coding RNAs can also affect the transcription of TAAs by targeting their mRNA or regulating upstream signaling pathways. At the splicing level, some splicing factors and splice site mutations can lead to different splicing isoforms of TAA's mRNA, thereby changing the sequence or stability of the encoded protein. At the translational level, some signaling pathways and transcription factors can regulate the 5' uncapped structure (5'UTR) or 3' untailed structure (3'UTR) of TAAs mRNA, thereby affecting its interaction with initiation factors or a ribose combination of bodies. At the degradation level, some proteasome inhibitors or endoplasmic reticulum stress can affect the degradation rate and efficiency of TAA proteins. At the level of antigen presentation, the abnormal expression or function of some HLA molecules or molecules related to antigen processing and presentation can affect the cleavage of TAA proteins into peptides and loading onto HLA molecules, which are displayed to T cells on the surface of tumor cells.

Mechanism of Interaction Between TAAs and the Immune System

As tumor-associated antigens, TAAs can be recognized and responded to by the immune system, thereby causing tumor immune responses. First, TAAs need to be taken up by professional or semi-professional antigen-presenting cells (APCs), such as dendritic cells (DCs) or macrophages, and cross-presented to primary T cells, thereby activating specific CD8+ killer T cells (CTL) and CD4+ helper T cells (Th). This process involves the interaction between TAAs and T cell receptor (TCR) and HLA molecules. TCR is a specific receptor on the surface of T cells that recognizes and binds peptides presented by HLA molecules. HLA molecules are the homologues of the major histocompatibility complex (MHC) in humans and are divided into two classes, HLA-I and HLA-II. HLA-I molecules mainly present endogenous antigens to CD8+CTL, while HLA-II molecules mainly present exogenous antigens to CD4+Th. Different individuals have different types and polymorphisms of HLA molecules, which determine their binding ability and affinity for different antigenic peptides. Second, activated specific T cells need to migrate to the tumor site and have direct contact with and interaction with tumor cells. This process involves interactions between TAAs, immune checkpoints, and immune evasion. Immune checkpoints are co-stimulatory or co-inhibitory signaling molecules that regulate T cell activation and function, such as CTLA-4, PD-1, PD-L1, etc. When T cells come into contact with tumor cells, these immune checkpoints can be expressed or released by tumor cells or other immune cells, and bind to corresponding ligands on the surface of T cells or in solution, thereby inhibiting or promoting T cell responses. Immune escape refers to the phenomenon that tumor cells avoid being recognized and eliminated by the immune system in various ways, such as by down-regulating or mutating TAAs or HLA molecules, releasing immunosuppressive factors, inducing immune tolerance or immunosuppressive cells, and so on. Finally, after successfully recognizing and binding tumor cells, specific T cells will release effector molecules such as perforin and granzyme B, and induce tumor cell apoptosis through the Fas/FasL pathway or the TNF/TNFR pathway. At the same time, specific T cells will also release some pro-inflammatory factors such as IFN-γ, IL-2, etc., and regulate the activation and proliferation of their own or other immune effector cells through positive feedback. These processes together constitute the role and impact of TAAs in the tumor immune microenvironment.

Applications of TAAs in Tumor Diagnosis, Prognosis Assessment, and Individualized Treatment

Because TAAs are highly immunogenic and tissue-specific, they can be used as tumor markers for early detection, differential diagnosis, and monitoring of tumors. At present, there are many methods to detect the expression level of TAAs in serum or tissue, such as serological detection, immunohistochemical detection, and flow cytometry detection. These methods have certain sensitivity and specificity, but there are also some limitations, such as false positive or false negative results, cross-reactivity or heterologous antibody interference, sample storage, or processing conditions. Therefore, clinically, it is usually necessary to combine multiple TAAs or other biomarkers for comprehensive judgment. At present, some TAAs have been confirmed to have diagnostic value and clinical significance in different types of tumors, such as AFP in primary liver cancer, CEA in colorectal cancer, PSA in prostate cancer, and NY-ESO-1 in melanoma. However, since the expression level of TAAs is affected by many factors and does not fully reflect the biological behavior and clinical characteristics of the tumor, individual differences and other relevant factors need to be considered when using TAAs for tumor diagnosis.

Since TAAs are closely related to tumor development and immune response, they can be used as tumor prognostic indicators to evaluate tumor malignancy and therapeutic effect. In general, the expression level of TAAs has a certain correlation with clinical parameters such as tumor stage, grade, recurrence, and metastasis. Highly expressed TAAs may reflect the characteristics of tumor cell proliferation, poor differentiation, diverse mutations, or strong immune escape ability, suggesting a poor prognosis, while low-expressed or missing TAAs may reflect slow tumor cell proliferation and better differentiation, a single mutation, or weak immune tolerance, suggesting a better prognosis. In addition, TAAs can also be used as indicators to evaluate the effect of immunotherapy. Generally speaking, after receiving immunotherapy, if the expression level of TAAs decreases or disappears, it indicates that immunotherapy is effective; if the expression level of TAAs increases or persists, it indicates that immunotherapy is ineffective or resistant. At present, some TAAs have been confirmed to have prognostic value and clinical significance in different types of tumors, such as MAGE-A3 in non-small cell lung cancer, NY-ESO-1 in ovarian cancer, and CTAG1B in testicular cancer. However, not all types of TAAs show a consistent correlation with prognosis, and different types and subtypes of tumors, as well as other relevant factors, need to be considered when using TAAs for tumor prognosis assessment.

Moreover, TAAs are ideal targets for tumor immunotherapy, so they can serve as the basis for individualized therapeutic strategies. Individualized treatment strategies based on TAAs mainly include T cell transduction, mRNA or peptide vaccines, and monoclonal antibodies. Individualized treatment strategies based on TAAs have the advantages of strong pertinence, high safety, and good immune memory, but there are still some challenges and problems, such as identification and selection of TAAs, individual differences and tumor heterogeneity, immune tolerance, and toxic and side effects. To date, some individualized treatment strategies based on TAAs have entered the clinical trial stage and have shown good safety and efficacy in some types of tumors, such as NY-ESO-1 TCR-transduced T cells in multiple myeloma, MAGE-A3 mRNA vaccine in melanoma, and NY-ESO-1 monoclonal antibody in ovarian cancer. However, the clinical application of these strategies still needs further optimization and validation to improve their broadness and durability.

Table 1. Tumor-Associated Antigen Genes clinical research