450 Brookline Ave
Longwood Center 4115
Boston, MA 02215
United States of America
Research in the Barbie laboratory broadly focuses on the connection between tumor innate immunity and oncogenesis. It has become increasingly clear over the last several years that intrinsic resistance to PD-1 blockade and other cancer immunotherapies involves signaling pathways that regulate response to viruses and other pathogens. For example, certain chronic viral infections establish an immune suppressive state, ultimately by recruiting immune suppressive myeloid populations. Our research has centered around TBK1, a critical kinase involved in this innate immune signal transduction in viruses as well as cancer. Indeed, KRAS mutant lung and other cancers can co-opt TBK1 signaling to promote the production of these immune suppressive cytokines and chemokines, and we have demonstrated that combination therapies inhibiting TBK1 together with MEK or PD-1 inhibition can result in tumor regressions in a variety of mouse model systems. More recently we demonstrated that rewiring this cytokine circuitry by engaging specific viral signaling adaptors such as MAVS and STING can shift cytokine output and promote a type 1 interferon response downstream of the transcription factor IRF3. We have also identified specific cellular contexts, such as combined KRAS/LKB1 mutation in lung cancer, which actively silences STING in order to avoid this antiviral effector response. Thus, a particularly active area of research is to develop epigenetic therapies that re-engage STING and fuel this cytotoxic and immunogenic response. We also have a strong interest in precision immunotherapy more generally, especially as it relates to combination therapies, and are developing novel functional assays that will likely assist in deploying these treatments in the proper contexts, in order to maximize patient benefit.
William C. Hahn, MD, PhD is the representative at this institution.