HLA typing in adoptive immunotherapy and disease research

What factors determine an individual’s HLA type?

HLA (Human Leukocyte Antigen) types are determined by the specific combination of alleles inherited from an individual’s parents. This unique genetic makeup plays a crucial role in how our immune system recognizes self versus foreign entities.

HLA expression, which refers to the amount of HLA proteins on cell surfaces, is influenced by a range of factors:

• Genetic factors: Key proteins like CIITA and NLRC5 regulate HLA gene transcription, while variations in promoter regions and alternative splicing can affect protein production and structure. Additionally, factors such as DNA methylation and microRNA regulation can further modulate expression levels.
• Non-genetic factors: The stability of HLA molecules on the cell surface is critical; stronger peptide binding leads to longer retention. Cells also actively regulate HLA levels through internalization processes, which can be influenced by infections and the activation state of the cell.

Why is HLA type crucial in both basic and clinical research?

HLA type is crucial in both basic and clinical research, due to its impact on various areas of immunology and disease understanding.

For instance, HLA molecules are vital for presenting antigens to T cells, which helps basic researchers explore how the immune system recognizes foreign invaders or how pharmaceutical drugs can induce T cell activation. Clinically, accurate HLA typing minimizes organ rejection risks. Matching donor and recipient HLA types enhances transplant outcomes, while studies on mismatches inform risks like graft rejection and graft-versus-host disease. Furthermore, many HLA types are now linked to one’s risk for developing autoimmune diseases. Research aims to uncover these connections to better understand susceptibility and develop targeted therapies, such as those focusing on HLA-DR2 in multiple sclerosis.

Are HLA-typed cells currently used in clinical trials or approved therapies?

HLA-typed cells are used in many clinical trials. Historically, HLA typing was largely used to understand how the immune system may contribute to cancer risk or how successful a given cancer treatment could be. As such, many current clinical trials are exploring HLA type as an immunotherapeutic option for solid tumors, gliomas, human papillomavirus-related epithelial cancers and leukemia.

How is HLA typing used to predict susceptibility to autoimmune diseases?

HLA typing is crucial for predicting susceptibility to various autoimmune diseases as certain HLA alleles and haplotypes are linked to increased or decreased risk. For instance:

• Myasthenia gravis: Early-onset is associated with HLA-B8.
• Multiple sclerosis: Correlates with HLA-DR2.
• Rheumatoid arthritis: Linked to HLA-DR4.
• Type 1 diabetes: Associated with the DR3-DQ2 haplotype.
• Juvenile autoimmune thyroiditis: Also related to DR3-DQ2.

Ancestral haplotypes (AHs) further enhance predictive capabilities for autoimmune diseases:

• AH 8.1: Associated with systemic lupus erythematosus and type 1 diabetes.
• AH 7.2: Linked to systemic lupus erythematosus and multiple sclerosis but protective against type 1 diabetes.

While the exact mechanisms remain unclear, key factors include:

• Peptide presentation: Some HLA alleles may present self-peptides that trigger autoimmune responses, such as rheumatoid arthritis-associated alleles activating autoreactive T cells.
• Autoantibody production: Specific alleles can influence autoantibody generation, exemplified by HLA-DRB1*03 in Sjögren’s syndrome.
• HLA expression levels: Variations in expression can modulate immune responses and impact autoimmune risk.

How does HLA compatibility influence the outcome of immunotherapy?

HLA compatibility is a key factor influencing the effectiveness and safety of various immunotherapies. For example, HLA molecules play a vital role in immune recognition. Some tumors may downregulate HLA expression to evade immune detection, reducing susceptibility to immunotherapy. Specific types of immunotherapies and how HLA impacts the effectiveness are outlined below.

1. Adoptive T-cell therapy involves engineering T-cells to target tumors. The effectiveness of these T cells relies on the recipient expressing the appropriate HLA allele to present the targeted antigen. In allogeneic stem cell transplants, HLA mismatches can lead to graft-versus-host disease, making HLA matching essential to minimize risks.
2. The success and tolerance of immune checkpoint inhibitors may also be impacted by HLA type. While not extensively discussed, research suggests that specific HLA alleles may affect responses to immune checkpoint inhibitors, impacting both treatment efficacy and the likelihood of immune-related side effects.
3. HLA typing is crucial for designing effective cancer vaccines, ensuring that tumor antigens are presented in a way that resonates with the target population. Personalized vaccines can be tailored to present patient-specific neoantigens based on their HLA types.

What are the challenges and limitations of integrating HLA typing into clinical practice?

Integrating HLA typing into clinical practice holds significant promise for enhancing our understanding of disease susceptibility, treatment strategies and transplant compatibility. However, several challenges need to be addressed to fully realize its potential.

• Cost and accessibility: One major hurdle is the expense of high-resolution HLA typing, which can be prohibitive, especially in resource-limited settings. The good news is that advancements in cost-effective technologies, such as next-generation sequencing, could help make HLA typing more affordable and accessible to a wider range of patients. Another resource-saving approach would be to use HLA-typed human primary cells from prescreened donors; this can be resource-saving without any further in-house HLA screening.
• Complexity of the HLA system: The HLA system is incredibly complex and polymorphic, making accurate interpretation of results a challenge. This complexity requires specialized expertise to understand the clinical significance of different alleles and the development of standardized testing protocols across laboratories to ensure consistent and reliable results.
• Population-specific associations: Another challenge is that HLA allele frequencies and their associations with diseases can vary significantly among different ethnic groups. This variability limits the generalizability of findings, emphasizing the need for ethnicity-specific studies. Additionally, minority populations are often underrepresented in research, which can lead to gaps in knowledge and disparities in clinical applications.
• Incomplete predictive value: Even when strong associations exist — like the link between HLA-B*57:01 and abacavir hypersensitivity — it’s important to recognize that the positive predictive value is often incomplete. This means that while certain HLA alleles may indicate a higher risk for reactions, other genetic and environmental factors also play a crucial role.
• Variability in HLA expression: HLA expression levels can fluctuate due to genetic and environmental influences, complicating assessments of transplant risk and the prediction of antibody-mediated rejection.
• Off-target toxicity in immunotherapy: In adoptive T-cell therapy, T-cell receptors can sometimes cross-react with unrelated peptides on healthy cells, leading to potential off-target effects. Comprehensive preclinical screening is essential to identify these risks and minimize adverse outcomes.
• Ethical considerations: Lastly, ethical concerns, such as genetic discrimination and the need for informed consent regarding HLA typing results, must be carefully managed to ensure patient privacy.

This interview was made in collaboration with RegMedNet.

Our expert

Courtney obtained her PhD in 2019 in biomedical science with a focus on developmental neuroscience. She joined PromoCell as a Scientific Support Specialist in January of 2022 and became the US HLA Coordinator in April of 2022. She is dedicated to educating fellow scientists and has taken on many outreach endeavors for high school STEM, medical students and advanced researchers alike in the last 15 years. As such, she utilizes her passion for education to help PromoCell customers better understand cell culture techniques and how HLA typed cells can be added to or used in their research paradigms.