Grant: Travel Awards - Institute Community Support

Metastatic melanoma is a life-threatening skin cancer. The most common frontline treatment is immune checkpoint blockade (ICB), which helps the immune system recognize and attack tumors. While this therapy has improved outcomes for many patients, it often fails, and once resistance develops, treatment options are limited. Patients without common genetic mutations (such as BRAF) are especially vulnerable, as they lack effective alternatives when ICB no longer works. Our research identifies a new barrier to successful immunotherapy: a previously unrecognized subset of immune cells called CD11b-positive regulatory B cells. These cells act to suppress the body's cancer-fighting T cells, allowing melanoma to escape immune attack. We discovered that therapies designed to stimulate the immune system, such as CD40 agonist antibodies, can inadvertently increase these suppressive B cells, limiting their effectiveness. By combining CD40 agonists with drugs that block cancer growth pathways (rigosertib and trametinib), we were able to reduce the activity of these regulatory B cells, restore anti-tumor T cell function, and drive tumor regression in experimental models. Importantly, we confirmed that this new subset of regulatory B cells is present across multiple cancer types in patients, highlighting the broad impact of our findings. This discovery not only reveals a new mechanism of immune resistance but also points to a promising treatment strategy for patients who no longer benefit from standard immunotherapy. By targeting both the tumor and its suppressive immune environment, our work opens the door to more effective second-line therapies, offering hope for improved survival and quality of life in ICB-resistant advanced melanoma.