September 16, 2021, NEW YORK – Researchers led by Ludwig MIT Co-director Tyler Jacks have found that vaccinating against certain cancer antigens—telltale fragments of aberrant proteins that reveal cancer cells to the immune system—can reawaken dormant anti-tumor T cell populations, strengthen the overall immune response and shrink tumors in mice.
When cells turn cancerous, they produce randomly mutated proteins that can serve as individualized cancer antigens. T cells that recognize these “neoantigens” start destroying the cancerous cells that display them. But those T cells eventually experience a phenomenon known as “exhaustion,” in which they enter a lethargic and dysfunctional state. Additionally, previous studies have shown that of the hundreds of neoantigens found in most tumors, only a small subset generate a T cell response.
The study, reported September 16th in Cell, helps shed light on why that is. In experiments on mice with lung tumors, the researchers found that as tumor-targeting T cells arise, subsets that target different neoantigens compete with each other, eventually leading to the emergence of a dominant population of T cells. After these T cells become exhausted, they remain in the tumor microenvironment and suppress competing T cell populations that target different neoantigens.
Jacks—who is also the David H. Koch Professor of Biology at MIT and a member of the Koch Institute for Integrative Cancer Research—and his colleagues found that vaccinating mice with neoantigens targeted by the suppressed T cells rejuvenated those T cell populations and increased the breadth and functionality of the T cell response. When they used one of those neoantigens in combination with a dominant neoantigen to vaccinate mice with lung tumors, tumors shrank by an average of 27 percent. Neoantigens associated with the suppressed T cell responses tended to weakly bind the immune cells responsible for presenting the antigen to T cells. Jacks and colleagues suggest that inclusion of weak binders in neoantigen vaccines for humans may provide greater therapeutic benefit than previously appreciated.
After vaccination, the T cell population included a subset that has the potential to continuously refuel the response, which could allow for long-term control of tumors. These T cells also caried a marker of response to checkpoint blockade immunotherapy, suggesting a combination therapy for evaluation in future studies.
The release from which this summary is derived can be found here.