Understanding the importance of cancer neoantigens in designing personalized mRNA vaccines
Despite progress made, a major hurdle of high-efficacy cancer vaccines is the identification of neoantigen proteins unique for cancer cells but not for healthy cells. This unique cancer identification ensures precision targeting of cancer cells only while sparing healthy cells. Why is it so challenging to identify cancer-specific molecular targets?
Two hallmarks of cancer play a critical role in impeding optimal cancer neoantigen identification, discussed below.
- The time factor. Cancer cells are normal cells that have gone awry in cell growth, differentiation, and movement. Cancer cells possess limitless replication potential, defying growth inhibition instructions, and are capable of making new blood vessels to pave the way for metastasizing to distal cells, tissues, and organs. Precisely because cancer cells are derived from normal cells, many antigen proteins on cell surfaces are shared between cancer and normal cells. Vaccines against cancer must be designed using antigens that are unique for cancer cells. Cancer cells’ normal origin makes it difficult.
- The spatial factor. In parallel to the cancer temporal factors described above, spatial factors can also pose challenges to optimal cancer vaccine design. Malignant tumors exist in a community of molecules called tumor microenvironment (TME). Within the TME, centering around and mingling with are a plethora of immune cells, fibroblasts, and cancer stem cells. Immune cells, side by side with tumor cells, include immune-boosting cells (such as macrophages) and regulatory T cells that function to tone down the host immune response. When it comes to tumor size, the bigger the tumor sphere, the tougher it is to treat because large tumors harbor more regulatory T cells that actively suppress immune functions and activities. Besides regulatory T cells, there are also cancer stem cells (CSC) within the TME. CSC has been demonstrated to turn mildly growing breast cancer cells into aggressively proliferating breast cancer cells with greatly enhanced metastatic potential.
To summarize
Accurate and efficient identification of cancer neoantigen proteins is an extremely challenging task stemming from:
- Cancer cells share a lot of similarities with normal healthy cells.
- As the tumor evolves, the neoantigens may also evolve.
- Interfacing and interacting with different cell types, especially cancer stem cells, adds another layer of complexity for cancer neoantigens.
The combination of time and spatial factors collectively contributes to an extremely complex landscape of cancer neoantigens. Artificial intelligence (AI) technologies are hopeful in assisting us in identifying patterns and visualizing trends concerning cancer neoantigens.
In light of the complexities of cancer, an ideal cancer vaccine may or may not be adequate, especially for patients with underlying immune conditions with weakened cytotoxic T cell (CTL) functional activities. It is well known that the elderly population suffers from a naturally occurring phenomenon of age-related shrinkage of the thymus gland. A non-fully functional thymus negatively impacts T cell function. Accordingly, elderly cancer patients are likely to respond to cancer vaccine-induced immune response against cancer differently from the younger generations. Taking into account all of the above factors in different dimensions, to tackle cancer most effectively, it is best to combine cancer vaccines with conventional treatment modalities especially immune checkpoint inhibition to create the most optimal molecular environment for patients’ T cells to robustly respond to cancer vaccine.21
21. Wang B, Pei J, Xu S, Liu J, Yu J. Recent advances in mRNA cancer vaccines: meeting challenges and embracing opportunities. Front Immunol. 2023;14:1246682. Published 2023 Sep 6. doi:10.3389/fimmu.2023.1246682
