What is antigen presentation?
Our immune system has various ways to protect us from pathogens. One of them is adaptive immunity; it mounts immune responses that are specialized, and targeted at a specific pathogen only. But how does that work and how can the immune system discriminate between different pathogens? The pathway that is responsible is called MHC class I antigen presentation pathway (Bjorkman et al. 1987a,b). It sounds complicated, but it is actually very simple: proteins inside the cell are constantly degraded to be recycled. A fraction of those degradation products, which are shorter peptides of about 8 − 11 amino acids, are not recycled, but instead are used by the immune system (Michalek et al. 1993). They bind to a peptide receptor called MHC class I molecule (MHC-I), travel to the cell surface, and are displayed for some time by antigen presenting cells.
Antigen presenting cells
Almost all nucleated cells display MHC-I molecules at the cell surface, there are however cells of the immune system that are specialized on antigen presentation, they are professional antigen presenting cells (Shastri & Yewdell 2015). Other cells of the immune system, like T cells or NK cells, survey those antigen presenting cells. If the displayed peptide is derived from a naturally occurring protein the immune system senses the surveyed cell is intact and functioning. However, if the peptide is derived from a virus, the T cell will sense that as a danger signal, and will proceed to kill the virus infected cell (Shastri et al. 2002). Obviously, I painted a very simplified picture, so I will explain a few of the key components and stages before talking about cancer immunotherapy: MHC-I molecules, peptide generation, loading and transport of the complex.
MHC-I molecules are peptide receptors that can bind peptides 8−11 amino acids long (Bjorkman et al. 1987b). What is special about them, is that they are the most polymorphic genes in the human genome, there are over 5000 individual variants and they vary immensely between individuals and populations (Klein 1986, Kulski et al. 2002, Kelley et al. 2005). Every person has between 3 and 6 different variants and they are different mainly in the part of the molecule that binds peptides. This means that every MHC-I molecule is able to bind its own set of peptides generating a unique complex. This way our total pool of MHC-I molecules protects against a variety of diseases.
Where do the peptides that bind to MHC-I molecules come from and how are they generated? Proteins in the cytoplasm are broken down into smaller fragments by the proteasome, a big protein degradation complex (Gromm e & Neefjes 2002). Those peptides are then transported into the endoplasmic reticulum by the TAP transporter, a kind of molecular pump, where they can be loaded onto MHC-I molecules (Gromme & Neefjes 2002). In the ER there are different enzymes that can further trim the transported peptides prior to loading and therefore further contribute to the diversity of peptides generated (Nagarajan et al. 2016).
MHC-I loading and transport
Antigen presenting cells go to great lengths to ensure that MHC-I molecules are loaded with the correct peptide. After loading MHC-I molecules undergo rigorous quality control, so that only stable complexes end up at the cell surface. The first step in this process is the peptide loading complex (PLC). It is a multi protein complex that stabilizes MHC-I molecules and facilitates loading. One of the molecules within the PLC, tapasin, competes with bound peptides, and has the ability to dissociate low-affinity peptides from MHC-I molecules. Only when a medium/high-affinity peptide is bound the complex will leave the PLC (Blees et al. 2015). Following the secretory pathway from the ER through the Golgi to the cell surface the peptide-MHC complex encounters one additional quality control checkpoint. A protein called TAPBPR, that is fairly similar to tapasin, also competes with the bound peptide (Hermann et al. 2015). If the peptide that is bound to MHC-I does not have a high enough affinity, it will dissociate and the empty MHC-I molecule will be sent back to the PLC to be loaded with a new peptide. MHC-I molecules can be found on almost every nucleated cell in the body, including cancer cells. This makes them an excellent target for therapies (Snyder et al. 2014).
Antigen presentation and cancer (immunotherapy)
So how does this pathway link to cancer immunotherapy? It was long be- lieved that the immune system tells apart ”self” from ”non-self” because it is trained early in life not to attack the cells of your own body . Since cancer cells come from your own body, you would assume that the immune system cannot detect cancer. However, this idea was amended as there are numerous examples of the immune system recognizing ”self”. The current notion is that the immune system is there to differentiate between harmless and potentially harmful signals, which can include either proteins that are expressed in much higher abundance than they normally would, or proteins that bear mutations for example due to cancer (Matzinger 1994, Granados et al. 2015). It was also shown that the immune system is able to start an immune response towards cer- tain cancers, however, it is not powerful enough to fight the cancer completely (Banchereau & Palucka 2005). This is due to a number of reasons, including the high mutation rate of cancers. Peptides that are generated from proteins that bear mutations are called ”tumor neoantigens”.
There are currently hundreds of research groups and companies racing to identify tumor neoantigens and to build algorithms that accurately predict which peptides will be generated and bound to MHC-I (Editorial 2017, Wang & Wang 2016, Schumacher & Schreiber 2015). However, there are numerous challenges in this endeavour: First, MHC-I molecules are highly diverse and sufficient data are lacking for many of them. Another issue is that many predicted peptides cannot be identified in tumor samples, or they fail to elicit T cell responses. This might be due to different reasons, one of which is that the rules of peptide selection are still poorly under- stood. For example, only recently was a new quality control checkpoint in the MHC-I antigen presentation pathway identified that substantially influences the peptide repertoire (Neerincx et al. 2017). Therefore, there needs to be a much deeper understanding of peptide selection and the antigen presentation path- way to make cancer immunotherapy as effective as it can be. Tumor neoantigen discovery, and systematic understanding of the rules of peptide selection, will lead to personalized cancer immunotherapies that boost the patient’s immune system and help them fight cancer.
Banchereau, J. & Palucka, a. K. (2005), ‘Dendritic cells as therapeutic vaccines against cancer.’, Nature reviews. Immunology 5(4), 296–306.
Bjorkman, P. J., Saper, M. A., Samraoui, B., Bennett, W. S., Strominger, J. L. & Wiley, D. C. (1987a), ‘Structure of the human class I histocompatibility antigen, HLA-A2’, Nature 329(6139), 506–512.
Bjorkman, P. J., Saper, M. A., Samraoui, B., Bennett, W. S., Strominger, J. L. & Wiley, D. C. (1987b), ‘The foreign antigen binding site and T cell recogni- tion regions of class I histocompatibility antigens.’, Nature 329(6139), 512–8.
Blees, A., Reichel, K., Trowitzsch, S., Fisette, O., Bock, C., Abele, R., Hummer, G., Sch ̈afer, L. V. & Tamp ́e, R. (2015), ‘Assembly of the MHC I peptide- loading complex determined by a conserved ionic lock-switch’, Scientific Re- ports 5, 17341.
Editorial (2017), ‘The problem with neoantigen prediction’, Nature Biotechnol- ogy 35(2), 97–97.
Granados, D. P., Laumont, C. M., Thibault, P. & Perreault, C. (2015), ‘The nature of self for T cells-a systems-level perspective’, Current Opinion in Immunology 34, 1–8.
Gromm ́e, M. & Neefjes, J. (2002), ‘Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways’.
Hermann, C., Trowsdale, J. & Boyle, L. H. (2015), ‘TAPBPR: A new player in the MHC class I presentation pathway’, Tissue Antigens 85(3), 155–166.
Kelley, J., Walter, L. & Trowsdale, J. (2005), ‘Comparative genomics of major histocompatibility complexes’.
Klein, J. (1986), ‘Antigen-major histocompatibility complex-T cell receptors: inquiries into the immunological m ́enage `a trois.’, Immunologic research 5(3), 173–90.
Kulski, J. K., Shiina, T., Anzai, T., Kohara, S. & Inoko, H. (2002), ‘Com- parative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.’, Immunological reviews 190(1), 95–122.
Matzinger, P. (1994), ‘TOLERANCE, DANGER, AND THE EXTENDED FAMILY’, Annu. Rev.lmmunol 12, 991–1045.
Michalek, M. T., Grant, E. P., Gramm, C., Goldberg, A. L. & Rock, K. L. (1993), ‘A role for the ubiquitin-dependent proteolytic pathway in MHC class I-restricted antigen presentation’, Nature 363(6429), 552–554.
Nagarajan, N. A., de Verteuil, D. A., Sriranganadane, D., Yahyaoui, W., Thibault, P., Perreault, C. & Shastri, N. (2016), ‘ERAAP Shapes the Pep- tidome Associated with Classical and Nonclassical MHC Class I Molecules.’, Journal of immunology (Baltimore, Md. : 1950) .
Neerincx, A., Hermann, C., Antrobus, R., van Hateren, A., Cao, H., Trautwein, N., Stevanovi?, S., Elliott, T., Deane, J. E. & Boyle, L. H. (2017), ‘TAPBPR bridges UDP-glucose:glycoprotein glucosyltransferase 1 onto MHC class I to provide quality control in the antigen presentation pathway’, eLife 6, e23049.
Schumacher, T. N. & Schreiber, R. D. (2015), ‘Neoantigens in cancer im- munotherapy’, Science 348(6230), 69–74.
Shastri, N., Schwab, S. & Serwold, T. (2002), ‘Producing nature’s gene-chips: the generation of peptides for display by MHC class I molecules’, Annu Rev Immunol 20(1), 463–493.
Shastri, N. & Yewdell, J. W. (2015), ‘Editorial overview: Antigen processing and presentation: Where cellular immunity begins’, Current Opinion in Im- munology 34, v–vii.
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., Walsh, L. A., Postow, M. A., Wong, P., Ho, T. S., Hollmann, T. J., Bruggeman, C., Kannan, K., Li, Y., Elipenahli, C., Liu, C., Harbison, C. T., Wang, L., Ribas, A., Wolchok, J. D. & Chan, T. A. (2014), ‘Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma.’, The New England journal of medicine 371(23), 2189–2199.
Wang, R.-F. & Wang, H. Y. (2016), ‘Immune targets and neoantigens for cancer immunotherapy and precision medicine’, Nature Publishing Group 27(1), 11– 37.