The human leukocyte antigen (HLA) system plays a critical role in immune surveillance, not only for the response to pathogens but cancer as well. Many emerging cell and immune therapies for cancer leverage antigen presentation mediated by HLA to enhance the immune system’s ability to recognize and destroy cancerous cells.
Improved scientific knowledge in this area will provide a stronger foundation from which we can build new and more effective cell and immune-based therapies. In this article, we explore the basic functions of HLA in immune response and how current immunotherapy approaches relate to HLA expression.
Immune Recognition of Cancer – A Critical Role for HLA
Key attributes of cancer include proliferation, immortalization, metastatic potential, and evasion of immune recognition.[1] Many of the genetic changes (mutations) that drive cancer create new antigens (neoantigens) that can be presented by HLA molecules and serve as a target for the immune response.
Although HLA-mediated presentation of neoantigens has been well described, research is ongoing to better understand how to more effectively generate a cancer-directed immune response and the mechanisms of cancer immune evasion, including the inhibition of HLA protein expression to prevent neoantigen recognition.[2]
The loss or down regulation of HLA class I molecules in tumor cells has been shown to be an important immune escape mechanism as this prevents the activation of a cytotoxic T cell response.[3]
Another way cancers evade the immune system is by impairing HLA class II expression which affects the antigen-presenting capability of antigen presenting cells.[4]
Genetic mutations that can occur within the HLA loci also have implications for immune recognition and the design of cancer vaccines and immunotherapies.
HLA and Cell Therapy
Enhancing T cell recognition of cancerous cells is a strategy utilized in several types of cell therapies. The most common approach relates to adoptive cell therapy (ACT) with antigen-specific receptors. Several types of ACT currently exist:
- Chimeric antigen receptors (CAR) T cell therapy – artificial receptors are designed to bind to certain proteins on cancer cells which will induce activation of specially engineered T cells.[5] CAR-T cells do not typically depend on recognizing HLA proteins, rather they are targeted to specific cell surface proteins (CD19, for example) that are expressed by the cancerous cells.
- T cell receptor (TCR) therapy – infusion of donor T cells with the ability to recognize HLA-bound neoantigens expressed by cancerous cells in the patient.[6]
- Tumor-infiltrating lymphocyte (TIL) therapy – involves the isolation, expansion, and stimulation of naturally occurring T cells in the patient that have already infiltrated and responded to their specific tumor. These tumor-specific T cells are then re-infused into the patient to effectively seek out and destroy the patient’s cancer.[7]
Although cell and immune therapies hold tremendous potential in treating cancer, immune evasion resulting from the genetic loss of some or all of the HLA molecules in the malignant cells is still a major hurdle that researchers must overcome.[8]
Want to Learn More?
Changes in HLA expression are a key factor to consider for cell- and immune-based immunotherapy strategies.[9] Therefore, understanding the complex interplay between HLA and neoantigen presentation is critical to developing more effective cell therapies. For more information on the HLA system and its role in immunotherapy research, check out our related blog posts.
At Cytologics, we specialize in supplying HLA-typed PBMCs and isolated immune cells for drug discovery. We understand that HLA data is critical to your experiments and we can help identify samples which meet your needs. Contact us today to discuss how we can support your research with HLA-typed immune cell products.
