Towards Better Cancer Vaccines via Identification of Important Neoantigens and T Cell Populations
Tumor cells have identifying surface markers that the immune system can in principle attack, but vaccination against those surface markers in order to encourage an anti-tumor immune response has been hit and miss. Researchers here dig deeper into the mechanisms that may explain this variability in response, and thus allow a more viable approach to patient-specific cancer vaccines that will more effectively rouse the immune system to target cancerous cells.
When cells begin to turn cancerous, they start producing mutated proteins not seen in healthy cells. These cancerous proteins, also called neoantigens, can alert the body's immune system that something has gone wrong, and T cells that recognize those neoantigens start destroying the cancerous cells. Eventually, these T cells experience a phenomenon known as "T cell exhaustion," which occurs when the tumor creates an immunosuppressive environment that disables the T cells, allowing the tumor to grow unchecked.
Scientists hope that cancer vaccines could help to rejuvenate those T cells and help them to attack tumors. In recent years, they have worked to develop methods for identifying neoantigens in patient tumors to incorporate into personalized cancer vaccines. Some of these vaccines have shown promise in clinical trials to treat melanoma and non-small cell lung cancer. "These therapies work amazingly in a subset of patients, but the vast majority still don't respond very well. A lot of the research in our lab is aimed at trying to understand why that is and what we can do therapeutically to get more of those patients responding."
Previous studies have shown that of the hundreds of neoantigens found in most tumors, only a small number generate a T cell response. Now a new study helps to shed light on why that is. In studies of mice with lung tumors, the researchers found that as tumor-targeting T cells arise, subsets of T cells that target different cancerous proteins compete with each other, eventually leading to the emergence of one dominant population of T cells. After these T cells become exhausted, they still remain in the environment and suppress any competing T cell populations that target different proteins found on the tumor. However, researchers found that if they vaccinated these mice with one of the neoantigens targeted by the suppressed T cells, she could rejuvenate those T cell populations. "If you vaccinate against antigens that have suppressed responses, you can unleash those T cell responses. Trying to identify these suppressed responses and specifically targeting them might improve patient responses to vaccine therapies."