In April of 2019, my friend started a campaign of saving her son at Go Fund Me.com (1). Her son was a star football player at his high school. Regrettably he was diagnosed with Non-Hodgkin’s Lymphoma, and had to give up his high school life and focus on chemotherapy treatment. He recovered from lymphoma quickly, started training again, with support from his mother who trained him. He came back to the field at the end of the season; unfortunately, the physicians found that the lymphoma had returned. Currently they are seeking a bone marrow transplant, specifically looking for a human leukocyte antigen (HLA) type matching donor.
What is HLA? Since I began working on the cancer neoantigen vaccine project at CureScienceTM, and I heard the anacronym “HLA” many times. Red blood cells have blood types such as ABO, Lewis antigen, Rh type, and so on. On the other hand, white blood cells also have blood types on the cell surface, called HLA types. The protein molecules presenting HLA types are major histocompatibility complex (MHC) class I and MHC class II. The variable region of MHC a and ß chains present polymorphism of peptide sequences, the diversity may be more than a million. MHC are presented on the surface of most of the nucleated cells in addition to leukocytes and platelets, expressing self/non-self-identity, thus it is the major cause of organ transplant rejection. In human beings, MHC is generally recognized as human leukocyte antigens (HLA).
The HLA gene complex resides within human chromosome 6 and contains genes spanning about 3.6 mega base pairs (Fig. 1, Ref. 2, 3). MHC (HLA) class I complex consist of HLA-A, HLA-B and HLA-C gene products. When pathogens such as viruses or various bacteria infect the cells, or cells transformed into cancer, cytosolic foreign antigen proteins are ubiquitinated, digested by proteasome to small peptides of 8~10 amino acids, then transported into the endoplasmic reticulum (ER) by transporter antigen processing (TAP). MHC Class I a and ß chains are synthesized in the ER and the digested foreign peptide combines with the MHC Complex. The resulting complex is transported to the cell surface. T-cell receptors (TCR) of cytotoxic T-lymphocytes (CD8+ T-cells) recognize this MHC Class I Complex. When a cytotoxic T-Cells TCR docks to an MHC Class I complex with the peptide, cytotoxic T-Cells triggers the cancer cells or infected cells to undergo apoptosis, mediating cellular immunity (3).
The MHC Class II complex is expressed mostly on Antigen Presenting Cells (APC) such as macrophage, dendritic cells, and lymphocytes. Pathogens or foreign antigens outside of cells are phagocytosed by these APC, digested into small peptide fragments in the endosome. The amino acids length of these fragments is 15~24 amino acids. These fragments form a complex binding to the cleft of synthesized MHC Class II molecules a and ß chain. The complex is then transported to the cell surface. In the case of MHC Class II, the cell surface complex docks with the Helper T-Lymphocyte (CD4+ T-Cell) which elicits activation of CD4+ T-cells and induces cytokine release, activates other cytotoxic T-cells or B-Cells (antibody production) to eliminate matching pathogens. The MHC Class II molecules are mainly coded by genes HLA-DQ, DR and DP.
Each human individual carries a set of MHC molecules inherited from the father, and another set from the mother. These genes are highly polymorphic, 19,031 alleles of class I HLA and 7,183 of class II HLA are deposited for human in IMGT database. This polymorphism creates a diversity of binding pockets in the MHC complex, enabling the MHC complex to present all kinds of antigens. In other words, each individual presents a different mechanism to combat diseases, thus strong individual survives for the next generation in terms of evolution.
In addition to classes I and II, other immune proteins outside of antigen presentations in the region are classified as MHC class III molecules. There are more than 30 MHC (or HLA) alleles (4), and each allele present thousands of polymorphism. This complexity leads to rejection issues with regard to bone marrow and organ transplants. Bone marrow transplant or hematopoietic stem cells transplant is a powerful solution to cure certain type of lymphoma in patients who cannot produce blood cells on their own. Nearly 80 % of hematopoietic stem cells transplants are peripheral blood stem cells transplants similar to blood donation. There is significantly less stress on the donors compared to taking bone marrow from a donors’ hip bones. If your blood can save a life of somebody who matches your HLA blood type, it would be a worthy cause to considering registering with the “Be the Match” as a donor (5).
With regard to the development of a cancer neoantigen vaccine, polymorphism of HLA could be advantageous or at least should be a major consideration when designing a personalized vaccine. Next Generation Sequencing (NGS) can analyze the sequence of the RNA or DNA of a patient’s tumor and normal DNA, predict binding affinities to MHC class I or II by bioinformatics, design unique peptide fragments tailored to every patient needs. These peptides present the unique portion of individual’s cancer binding to MHC molecules and activate unique sets of T-cells in patients leading to cure of cancer (6). CureScienceTM and their collaborators are advancing neoantigen vaccine development. If you are interested in participating in neoantigen vaccine treatment, please contact us at www.curescience.org.
Written by: Misa S. Anekoji, Ph.D.
Keywords: HLA, MHC, hematopoietic stem cells, transplant, neoantigen vaccine
References:
6. MM. Richters et al., “Best practices for bioinformatic characterization of neoantigens for clinical utility”, Genome Medicine 11:56 (2019)