A Novel Strategy to Improve Peptide Based Cancer Vaccines through Molecular Mimicry

By Ashish Ramlal

Cancer remains a leading cause of mortality worldwide. The therapeutic options to treat cancer are often limited, which reduces the chance to successfully treat patients. To tackle this health problem, interventions are developed such as immunotherapies to target or influence the immune system¹. For example, cancer vaccines that are potentially able to initiate anti-tumour responses². These vaccines often bring minimal side-effects, which isn’t the case with conventional cancer treatments². Since these vaccines initiate immune responses that could both target cancer and healthy cells, they are considered a double edged sword. Nevertheless, with the right improvement these vaccines can be a prominent tool for successful immunotherapy and used to treat various cancers, such as melanoma and breast cancer with limited side-effects. In this article, potential avenues and challenges in this field will be discussed, with an introduction to molecular mimicry and how it can be used to enhance the development of successful cancer vaccines.

Peptide-based cancer vaccines

Most cancer immunotherapies aim to enhance the anti-tumour response through the activation of an immune cell type known as cytotoxic T-Cells (CTLs)^3,4. These immune cells are able to kill cells upon the recognition of their target cells. Cancer vaccines can be delivered in the form of peptides (small proteins). Peptide-based cancer vaccines induce an anti-tumour memory response that potentially targets cancer². Since cancer cells are known to be genetically unstable, they could express various abnormal proteins in high numbers that are normally limited in healthy cells. These vaccines have the potential to initiate the immune system in such a way that memory is achieved, to control cancer cells and to prevent cancer relapse⁵. Since the peptides present on cancer cells vary among cell types and individuals, this strategy is a form of personalised immunotherapy².

The selection of peptides subsequently used in vaccines is the most critical aspect in the process of developing superior cancer vaccines. It is essential that the selected peptide is present on the cancer cell, to ensure that a CTL can recognise and target these cells⁵. There are different types of cancer antigens, which are classified as tumour-associated antigens (TAAs) or tumour-specific antigens (TSAs). TAAs are derived from the cell metabolism; they are expressed in healthy cells and highly expressed in cancer cells. Our B and T immune cells that are primed to recognise these self-antigens are normally eliminated, by mechanisms that select for self-reactive B and T cells, the central tolerance mechanisms, which prevents autoimmunity⁶. Therefore, it is critical for cancer vaccines that include TAAs to overcome the central tolerance mechanisms. However, these vaccines also have a risk of inducing immune responses that initiate CTLs to target healthy cells that also express these specific peptides, which is a process referred to as autoimmunity⁵. Furthermore, these central tolerance mechanisms could prevent TAAs vaccines from being effective. Current cancer vaccines harbour these risks and are considered as a double edged sword. Therefore, selecting the right antigen is essential in the development of cancer vaccines.

Improving immunotherapies through molecular mimicry

A novel strategy to overcome these challenges is molecular mimicry⁷. Pathogens have developed molecular mimicry as a way to escape the host immune response. These pathogens contain peptides from their own metabolism that have high similarity (homology) or are almost identical to peptides of the infected host. By containing homologous host peptides the pathogens are able to escape immune response since they are not considered foreign by the immune system⁷. However, this term also describes the mechanism by which infectious agents can cause autoimmunity by homology between their infectious exogenous (foreign) peptides and host peptides (Figure 1). This homology can result in cross-reactive responses that initiate the activation of CTLs to target the pathogen,  infected cells and healthy cells⁸ (Figure 1). Therefore, molecular mimicry is involved in both the immune response and autoimmunity, which determines the pathogenesis of diseases⁷. Nevertheless, through molecular mimicry peptides can be used to ensure that CTLs could target cancer cells instead. For example, by using pathogen derived antigens that are non-self antigens and only homologous towards TAAs⁷. This would improve the required responses necessary to initiate the activation of CTLs and the targeting of specific cancer cells that contain the TAAs homologous to the non-self antigens. Overall, this will prevent the risk of autoimmunity and could overcome the current limitations of cancer vaccines.

Targeting cancer cells through the activation of cytotoxic T-Cells

Most of the current immunotherapies aim to enhance the anti-tumour response through the activation of CTLs^3,4. There are complex processes required to initiate responses to target cancer cells. Dendritic cells (DCs), also known as antigen presenting cells (APCs), are part of our innate immune system and are able to take up peptides⁹. APCs can recognise and internalise small exogenous peptides, which are also referred to as antigens¹⁰. These antigens are processed through DCs and presented on major histocompatibility complex (MHC) class I molecules (Figure 2). These molecules are expressed on the cell surface and present the processed antigens that were first internalized by the DCs. This is a process referred to as cross-presentation. These cross-presented peptides can be recognised by naïve (inactive) CD8+ T-cells (CTLs). This specific priming process initiated by DCs, ensures that naïve CD8+ T cells become activated CTLs, upon antigen recognition¹¹. Furthermore, when cells are unhealthy they can also directly present pathogenic or cancer peptides on MHC class I molecules, with peptides derived from their own metabolism. When CTLs are primed after cross-presentation with a specific antigen, they can recognize the same antigen that is presented on the unhealthy cells.

Upon recognition of the peptide on cancer cells, the activated CTLs are able to target the cancer cells (Figure 2). The effector functions of CTLs can induce apoptosis (regulated cell death) of targeted cells through the usage of various proteins (Figure 2). Therefore, both antigen uptake and cross-presentation are critical for the outcome of cancer vaccines that rely on initiation of the CTLs to target cancer cells⁹.

The challenges of existing immunotherapies

Further research is necessary to find out how the cross-presentation pathway is precisely regulated and how this contributes to therapy efficiency¹⁰. This could allow the development of better vaccines that can be personalized to treat various cancer types. Exogenous antigens that are taken up by APCs are not always cross-presented, causing challenges for cancer vaccines that are dependent on the antigen cross-presentation and antigen-uptake processes. This prevents cancer cells from being targeted by CTLs. These challenges have not been solved yet, because the exact mechanisms involved in cross-presentation are not fully understood. For example, it remains unclear how antigens are processed in the cells and how cross-presentation is regulated¹⁰. In addition, exogenous antigens are often also trapped within specific departments of the cells and degraded, resulting in poor cross-presentation and low CTL activation. This is a serious problem for cancer vaccinations that are dependent on the uptake and presentation of peptides by APCs. For this reason, elucidating and exploiting cross-presentation and antigen-uptake has become beneficial to enhance immunotherapies¹⁰.

The prevention of cancer

To target cancer cells through our immune system at an early stage, it is necessary to establish a rapid anti-tumour response. This is possible through the usage of preventive cancer vaccines (Figure 3). The advantage of targeting cancer at an early stage is that the immune suppressive tumour environment has not been established^7,12. It is important that memory CD8+ T cell immunity is developed to cross-react and target cancer cell types containing specific homologous TAAs^7,12 (Figure 3). Memory CD8+ T cells are CD8+ T cells that are primed to target a specific antigen. Exposure to their corresponding antigen will induce effector functions¹³. Naturally this occurs through the exposure of pathogens, since there is homology between TAAs and antigens derived from pathogens^7,12 (Figure 3). This provides a natural library of memory CD8+ T cells that could prevent the growth of certain tumours (Figure 3). The extent of this natural library influences the outcome of cancer progression¹⁴. Furthermore, it is important to prevent the immune evasion of cancer cells, since cancer cells are known to be highly mutagenic. Immune evasion is one of the hallmarks for cancer and also poses a problem for many immunotherapies⁹. Such mutations can lead to the loss of specific antigens (exogenous peptides) in cancer cells, making specific cancer vaccines ineffective⁹. Therefore, establishing memory immunity early on can prevent cancer progression more efficiently. Ideally, the selected TAAs to target are expressed in different types of cancer, ensuring a preventive cancer vaccine that targets a wide variety of cancers^7,12.

All in all, more research is necessary to identify pathogen derived antigens homologous to only TAAs. This will be possible through the incorporation of molecular mimicry into the development of cancer vaccines. Further research is also necessary to enhance both the antigen uptake and presentation of these important peptides to improve the immune responses. Ultimately, this novel strategy, using peptide based cancer vaccines that can provide cancer patients a higher chance of recovery, could represent a breakthrough in cancer therapy.

About the Author

Further reading

1. Naran, K., Nundalall, T., Chetty, S., & Barth, S. (2018). Principles of immunotherapy: implications for treatment strategies in cancer and infectious diseases. Frontiers in microbiology, 9, 1-23. https://doi.org/10.3389/fmicb.2018.03158  ↩︎
2.  Gupta, M., Wahi, A., Sharma, P., Nagpal, R., Raina, N., Kaurav, M., … & Nissapatorn, V. (2022). Recent Advances in Cancer Vaccines: Challenges, Achievements, and Futuristic Prospects. Vaccines, 10(12), 2011. https://doi.org/10.3390%2Fvaccines10122011  ↩︎
3. Harryvan, T. J., Visser, M., de Bruin, L., Plug, L., Griffioen, L., Mulder, A., van Veelen, P. A., van der Heden van Noort, G. J., Jongsma, M. L., Meeuwsen, M. H., Wiertz, E. J., Santegoets, S. J., Hardwick, J. C., Van Hall, T., Neefjes, J., Van der Burg, S. H., Hawinkels, L. J., & Verdegaal, E. M. (2022). Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S. Journal for immunotherapy of cancer, 10(3), 1-18. https://doi.org/10.1136/jitc-2021-003591 ↩︎
4. Naran, K., Nundalall, T., Chetty, S., & Barth, S. (2018). Principles of immunotherapy: implications for treatment strategies in cancer and infectious diseases. Frontiers in microbiology, 9, 1-23. https://doi.org/10.3389/fmicb.2018.03158 ↩︎
5. Abd-Aziz, N., & Poh, C. L. (2022). Development of peptide-based vaccines for cancer. Journal of Oncology, 2022.  https://doi.org/10.1155%2F2022%2F9749363  ↩︎
6. Xing, Y., & Hogquist, K. A. (2012). T-cell tolerance: central and peripheral. Cold Spring Harbor perspectives in biology, 4(6), a006957. https://doi.org/10.1101/cshperspect.a006957 ↩︎
7. Tagliamonte, M., Cavalluzzo, B., Mauriello, A., Ragone, C., Buonaguro, F. M., Tornesello, M. L., & Buonaguro, L. (2023). Molecular mimicry and cancer vaccine development. Molecular cancer, 22(1), 75. https://doi.org/10.1186/s12943-023-01776-0 ↩︎
8. Rojas, M., Restrepo-Jiménez, P., Monsalve, D. M., Pacheco, Y., Acosta-Ampudia, Y., Ramírez-Santana, C., Leung, P. S. C., Ansari, A. A., Gershwin, M. E., & Anaya, J. M. (2018). Molecular mimicry and autoimmunity. Journal of autoimmunity, 95, 100–123. https://doi.org/10.1016/j.jaut.2018.10.012  ↩︎
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10. Embgenbroich, M., & Burgdorf, S. (2018). Current concepts of antigen crosspresentation. Frontiers in immunology, 9, 1-10. https://doi.org/10.3389/fimmu.2018.01643 ↩︎
11. Raskov, H., Orhan, A., Christensen, J. P., & Gögenur, I. (2021). Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. British journal of cancer, 124(2), 359-367. https://doi.org/10.1038/s41416-020-01048-4   ↩︎
12.  Tagliamonte, M., & Buonaguro, L. (2022). The impact of antigenic molecular mimicry on anti-cancer T-cell immune response. Frontiers in oncology, 12, 1009247. https://doi.org/10.3389/fonc.2022.1009247  ↩︎
13. Martin, M. D., & Badovinac, V. P. (2018). Defining Memory CD8 T Cell. Frontiers in immunology, 9, 2692. https://doi.org/10.3389/fimmu.2018.02692 ↩︎
14. Boesch, M., Baty, F., Rothschild, S. I., Tamm, M., Joerger, M., Früh, M., & Brutsche, M. H. (2021). Tumour neoantigen mimicry by microbial species in cancer immunotherapy. British Journal of Cancer, 125(3), 313-323. ↩︎