Inhibition of the p38MAPK Pathway to Increase Vaccine Responses in Breast Cancer

Can the tumor environment be altered to allow better leverage of mRNA vaccine technology?

When you’re infected by a virus or bacteria for the first time, it takes your immune system time to locate, mobilize, and eliminate the threat. However, if that same virus or bacteria attacks again, your immune system, having encountered this enemy before, is able to launch a more powerful and swift counterattack. Vaccination leverages this remarkable immunological memory by showing our immune system what a potential invader might look like, so if we’e exposed in the future, we experience a swift and robust defense. The power of vaccination was clearly demonstrated during the COVID-19 pandemic, where rapid vaccine development saved millions of lives worldwide.

Cancer researchers have long recognized the potential of vaccines but have faced significant challenges in using them against cancer. Two major hurdles are: 1) the immune system’s ability to recognize foreign invaders but its tendency to avoid attacking the body’s own cells (a process known as tolerance), making it difficult to detect cancer cells, which originate from our own tissues; and 2) tumors create environments that hinder the immune system’s ability to detect and destroy tumor cells. Advances in large-scale tumor sequencing are addressing the first challenge by identifying targets unique to cancer cells, but the second challenge remains formidable and is the focus of DR. Stewart’s project.

In the context of the immune system’s army, dendritic cells (DCs) serve as the skilled sentinels that instruct immune system T cells to kill specific targets. However, in tumors, DCs struggle to penetrate and effectively direct the killing of tumor cells. Dr. Stewart’s previous research found that activation of a protein called p38MAPK leads to the release of factors that can alter the activities of various cells, making a tumor’s landscape difficult to traverse and obscuring the DCs’ ability to gather intelligence and relay orders to the T cells. She will use her Fletcher Scholar’s Award to pursue the hypothesis that by inhibiting p38MAPK she can enhance the ability of DCs to perform their sentinel duties by improving their capacity to penetrate tumors and relay vital information back to the T cells.

Additionally, Dr. Stewart will explore the use of mRNA vaccine technology, most recently used for COVID-19 vaccines. mRNA vaccines offer rapid production and the ability to be adapted quickly, which is crucial for creating personalized cancer vaccines tailored to each patient’s unique tumor profile. In summary, her work aims to combine p38MAPK inhibition with vaccination to enhance the success of anti- cancer vaccines, potentially providing a powerful new tool in the fight against metastatic cancer.