Problem -- Cancer and the Immune System
What is Cancer?
Cancer is not one single disease, but a collection of diseases caused by uncontrolled cell growth. Instead of undergoing normal cell death, cancer cells continue dividing as long as nutrients are available. Over time, this uncontrolled growth can disrupt normal organ function and become life-threatening.
A common misconception is that cancer acts like a toxic chemical that directly destroys cells. In reality, cancer is a type of cell that fails to stop dividing when it should. Mutations in genetic information drive these abnormal growth patterns, making cancer cells difficult to track and eliminate.
According to the World Health Organization (WHO), cancer is a leading cause of death worldwide, responsible for nearly 10 million deaths in 2020. The most common causes of cancer death were:
- Lung: 1.80 million deaths
- Colorectal: 916,000 deaths
- Liver: 830,000 deaths
- Stomach: 769,000 deaths
- Breast: 685,000 deaths (WHO Fact Sheet, 2020)
This makes cancer not only a biological challenge but also one of the most pressing global health problems.
How the Immune System Detects Abnormal Cells
Antigens as "ID Cards"
Every cell produces proteins. These proteins are broken down into small fragments (peptides), which are displayed on the cell surface by MHC Class I molecules. These peptides act like ID cards, telling immune cells what is happening inside the cell (Neefjes 2011)(Rock 2016).
MHC Class I: The Display Platform
MHC Class I molecules are found on almost all nucleated cells. Their job is to present these peptide "ID cards" so that the immune system can recognize whether the cell is healthy or abnormal.
- Structure: The MHC I heavy chain contains three domains (α1, α2, α3) and associates with β2-microglobulin for stability.
- Function: The peptide-binding groove, formed by the α1 and α2 domains, determines what peptides are displayed.
If the peptide comes from a normal protein → the immune system leaves the cell alone.
If the peptide comes from a mutated protein, virus, or tumor-specific antigen → the immune system recognizes the cell as dangerous.
T-Cells: The Security Force
Cytotoxic T lymphocytes (CD8+ T-cells) patrol the body, scanning peptides bound to MHC I. When they recognize a peptide as "non-self," they are activated and kill the presenting cell (Dunn 2002).
Dendritic Cells: The Messengers
Dendritic cells capture antigens from tumors and bring them to lymph nodes, where they "train" T-cells to attack cancer cells (Chen & Mellman 2017).
Figure 1. Immune surveillance diagram
Why Cancer Escapes Detection
Cancer cells are not passive --- they evolve ways to hide:
- Weak MHC presentation: Tumor-derived peptides may not bind strongly to MHC I, making them poorly displayed (Rammensee 1999)(Trolle 2016).
- Loss of MHC molecules: Some tumors reduce or eliminate MHC expression altogether (Dunn 2002).
- Immunosuppressive environment: Tumors release molecules that suppress T-cell activity (Chen & Mellman 2017).
As a result, even though the immune system has mechanisms to detect abnormal cells, tumors often escape and continue to grow.
Why Current Cancer Treatments Are Not Enough
Chemotherapy
- Uses drugs to kill rapidly dividing cells.
- Problem: normal healthy cells also get killed → severe side effects.
Targeted Therapy
- Targets specific tumor proteins or pathways.
- Advantage: fewer side effects than chemotherapy.
- Limitation: can still damage healthy cells near tumors.
Immunotherapy
- Uses the patient's immune system to fight cancer.
- Examples: checkpoint inhibitors, CAR-T cells, cancer vaccines.
- Limitations: depends heavily on effective antigen presentation by MHC. If MHC display is weak, immunotherapy may fail (Schumacher & Schreiber 2015)(Sahin & Türeci 2018).
Figure 2. Comparison diagram of therapies
Different Immunotherapy Methods
- Cell Therapy: Immune cells (e.g., T-cells) are extracted, activated or engineered, then reintroduced. Effective but costly and not scalable.
- Monoclonal Antibodies: Block tumor proteins or immune checkpoints, helping T-cells respond better.
- Oncolytic Viruses: Engineered viruses that selectively infect and kill cancer cells.
- Immunomodulators: Drugs that stimulate or suppress immune system activity.
- Cancer Vaccines: Train the immune system using peptides or proteins from tumors.
These methods show promise but still face a key limitation: without strong MHC-peptide presentation, T-cells cannot respond effectively.
Our Idea -- Engineering MHC for Better Antigen Delivery
Our project begins with a very simple but powerful question: what if we could make cancer cells easier for the immune system to see? Normally, MHC Class I proteins display small fragments of proteins (peptides) on the surface of cells, like an ID card. T cells then scan these IDs to decide whether the cell is healthy or dangerous. The problem is that many cancer peptides do not bind strongly to MHC, so they are either displayed poorly or not at all. This means T cells never get the signal that something is wrong.
Instead of only changing the peptides --- which is what many cancer vaccine strategies try to do --- we decided to focus on the other side of the interaction: the MHC itself. Our idea is to engineer the MHC Class I protein so that it can hold onto tumor peptides more tightly and display them more reliably. By improving this natural "display system," we aim to make sure cancer cells cannot hide from the immune system.
To achieve this, we use a two-part approach. First, we apply computational protein design tools to predict changes (mutations) in the MHC heavy chain that could make the binding pocket more stable for tumor peptides. This is our design phase. Second, we put those designs to the test by synthesizing the modified DNA, expressing the proteins in bacteria, and then refolding them together with peptides in the lab. This allows us to compare how well the engineered MHC proteins perform compared to the unmodified wild-type versions.
The goal is not to invent an entirely new therapy on its own but to strengthen existing immunotherapies. Treatments like checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies all depend on proper antigen presentation. If MHC molecules show peptides more clearly, T cells can be activated more efficiently, and these therapies could work better in more patients.
In simple terms, our idea is like upgrading the "billboard" that shows cancer peptides to the immune system. A brighter, clearer display means T cells will recognize the threat more often, leading to faster and stronger immune responses. With this approach, we hope to contribute a foundational tool that researchers and clinicians can build upon to develop the next generation of cancer treatments.
This strategy could:
- Enhance the visibility of tumor antigens to the immune system.
- Improve the effectiveness of existing immunotherapies (checkpoint inhibitors, cancer vaccines, CAR-T).
- Create a general platform for antigen display technologies.
Why Our Project is Needed
The central question in cancer immunotherapy is:
How do we make tumor antigens visible enough for the immune system to act?
By directly improving MHC Class I function, we aim to address a bottleneck that limits many existing therapies. Our project contributes to:
- Better research tools for immunologists.
- More reliable cancer vaccines.
- Future therapies that work across different patients, regardless of individual MHC allele differences.
This work embodies the spirit of iGEM: using synthetic biology to design, build, test, and learn in order to solve global challenges.
References
- Schumacher, T. N., & Schreiber, R. D. (2015). Neoantigens in cancer immunotherapy. Science, 348(6230), 69--74.
- Sahin, U., & Türeci, Ö. (2018). Personalized vaccines for cancer immunotherapy. Science, 359(6382), 1355--1360.
- Neefjes, J., et al. (2011). Towards a systems understanding of MHC class I and class II antigen presentation. Nat Rev Immunol, 11(12), 823--836.
- Rock, K. L., Reits, E., & Neefjes, J. (2016). Present yourself! By MHC class I and class II molecules. Trends Immunol, 37(11), 724--737.
- Chen, D. S., & Mellman, I. (2017). Elements of cancer immunity and the cancer--immune set point. Nature, 541(7637), 321--330.
- Dunn, G. P., et al. (2002). Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol, 3(11), 991--998.
- Rammensee, H.-G., et al. (1999). SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics, 50, 213--219.
- Garboczi, D. N., et al. (1992). Assembly, specific binding, and crystallization of a human TCR--MHC complex. PNAS USA, 89(8), 3429--3433.
- Altman, J. D., et al. (1996). Phenotypic analysis of antigen-specific T lymphocytes. Science, 274(5284), 94--96.
- Trolle, T., et al. (2016). The length distribution of class I--restricted T cell epitopes. J Immunol, 196(4), 1480--1487.
- World Health Organization (WHO). (2020). Cancer Fact Sheet. Retrieved from: https://www.who.int/news-room/fact-sheets/detail/cancer
