What do puzzles and immunity have in common? The human leukocyte antigen (HLA) system of cell-surface proteins help to regulate the immune system. Yet particular antigens can make a crucial difference. Patients with certain HLA types are more likely to have autoimmune diseases, contract infectious disease or develop cancer. Now, through better understanding of HLA function, scientists are piecing together new cancer immunotherapies.


More than 250 genes on chromosome 6 are responsible for encoding MHC class I and II molecules.
HLA restriction: finding and binding
More than 60 years ago, researchers observed that blood serum from one person reacted with white blood cells of another person. This led them to identify the first HLA molecule, HLA A-2 (Dausset, 1958). By 1968, so many HLA antigens had been identified that the HLA Nomenclature Committee was founded, with the aim of giving official names to new HLA molecules (Thorsby, 2009). In the 1970s, the Nobel-prize winners Rolf Zinkernagel and Peter Doherty showed that MHC enabled T cells to recognize antigens. However, researchers needed another decade to discover the rules for the interactions between HLA proteins and T cells, and how to explain the phenomenon of HLA restriction (Bjorkman et al., 1987; Rammensee et al., 1986). In fact, T cells can recognize peptides only if they are bound to HLA molecules. These peptide-HLA complexes interact only with HLA-matched T cells that have the corresponding receptors.
But there are many more pieces to this complicated puzzle. Two main classes of MHC molecules, MHC class I (HLA-A, HLA-B, and HLA-C) and MHC class II (HLA-DP, HLA-DR, and HLA-DQ) exist. Located between the genes coded for MHC class I and II proteins on chromosome 6, is a cluster of genes for MHC class III proteins. These proteins are not involved in antigen presentation, but mainly serve as signals for intercellular communication. MHC class I proteins are expressed on all cells of the body, except for red blood cells, and these proteins bind peptides from within the cells. MHC class II proteins are usually on the cell surface of antigen-presenting cells (APCs) and bind antigens that have been phagocytosed and processed from outside the body.

Cytotoxic CD8+ T cells and helper CD4+ T cells work side by side to defend the body from viral infections and to eliminate cancer cells.
HLA and diseases: activating autoimmune responses
Yet the immune response can backfire and having a specific HLA allele can hang like the sword of Damocles over a person. “It is true that HLA molecules are key for a functioning immune system. Yet, certain HLA alleles are associated with distinct pathological conditions,” remarks Hamelmann. Autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, and Graves’ disease are related to certain HLA class I molecules. When cytotoxic T cells join in, they can spark the onset of the disease or worsen it. Variations in HLA class I genes can trigger autoimmunity, in particular, following bacterial or viral infections. Then the vicious circle becomes more vicious.
The two major histocompatibility complex (MHC) or human leukocyte antigen (HLA) classes are expressed on the surface of cells and form a groove where peptides can bind.
HLA and cancer: how cancer cells escape recognition
The HLA profile can initiate the onset of cancer, or influence the response to chemotherapy, especially in virally-associated cancers (Little et al., 1999). Carcinogenic viruses activate genes that allow cancer cells to escape immune surveillance and proliferate without control. Possible immune escape mechanisms include changes in the structure and function of HLA, loss of expression of tumor antigens, and production of immunosuppressive cytokines. How well cancer patients respond to immunotherapy also depends on their HLA type, as patients with certain HLA class I molecules tend to have better outcomes. In a recent study, scientists observed the response of 369 melanoma patients to immune checkpoint inhibitors. Patients with the HLA-B44 type lived longer than those with the HLA-B62 (Chowell et al., 2017).New therapeutic options: harnessing HLA for cancer immunotherapy

She knows her cells:
Dr. Lisa Hamelmann is a Product Manager. She knows how important HLA types are in physiology and in fighting diseases.
The body’s own peptides that are bound to HLA molecules on healthy cells usually don’t generate a T cell response. However, tumor cells contain additional tumor-specific peptides that aren’t present on normal cells. These tumor-associated antigens (TAA) can be encoded by mutated genes (neoantigens) or can be derived from proteins that are overexpressed in tumors. When presented by HLA molecules, TAA can activate cytotoxic T cells. These may be able to destroy the tumor cells before they proliferate or metastasize. The immune system’s ability to recognize TAA is where immunotherapy begins.
Stem-cell transplantation, a life-saving procedure for patients with hematological malignancies, found in bone marrow, for example, was one of the first attempts at immunotherapy. The success of a transplantation strongly depends on the HLA-compatibility between donor and recipient. If they are incompatible, this generates complex immune reactions. The body will reject the graft or cells will lose their function. To avoid rejection, as well as graft-versus-host-disease, HLA typing must be followed by matching of donor and recipient (Howard et al., 2016).
In cancer immunotherapy, neoantigens are very attractive targets. They are expressed only in malignant cells, and the T cell repertoire that recognizes them is not affected by central tolerance. Neoantigen-reactive T cells have been found in many tumors, and the number of neoantigens on cancer cells directly correlates to immunotherapy success (Karpanen and Olweus, 2017). However, sometimes autologous antigen-specific T cells don’t recognize neoantigens and they fail to stop cancer from spreading. This happens when T cells are inhibited or deleted by tolerance-inducing mechanisms.
Alternative approaches, such as using T cells from HLA-matched donors, can cure hematologic malignancies – because these cells recognize that polymorphic peptides in the donor and patient are different (Falkenburg, 2010). Adoptive immunotherapeutic approaches, as the transfer of CAR T cells, use genetically modified T cells from healthy (HLA-matched) individuals. The CAR T cells then respond to neoantigens that were ignored by the patient’s tumor-infiltrating T cells (Khalil et al., 2016). Even though neoantigens can be identified quickly, it takes time and resources to assess their immunogenicity. By finding tumor-specific biomarkers, along with greater understanding of each patient’s HLA type, researchers can slowly piece together the puzzle of possible therapies for each individual.
Scientific Poster: The human leukocyte antigen (HLA) complex
Refresh your knowledge on immunology and the human leukocyte antigen (HLA). Our poster provides an overview the genetic structure of the HLA complex, the major histocompatibility complex (MHC) classes, T cell activation and applications of that knowledge in cancer immunotherapy.
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