Interrogating the role of IFNgamma in promoting metastasis and immune evasion of triple negative breast cancer

Project Summary During metastatic spread, cells that have successfully metastasized to secondary sites must overcome both endogenous mechanisms of control as well as therapeutic interventions. Immune cells are an endogenous mechanism of control that are often reinvigorated by checkpoint blockade to great therapeutic benefit. One mechanism by which immune cells control the spread of both primary and metastatic tumors is through the delivery of cytokines, specifically type II interferons, the production of which is enriched following treatment. Interferon gamma (IFNγ) has been shown to play a role in both promoting and restricting tumor growth in primary cancers via overexpression of both MHC-I and PD-L1. However, its role in metastatic disease, particularly following treatment is less well understood. This work seeks to clarify the role of IFNγ in metastatic disease. Preliminary data indicates that in the context of triple negative breast cancer (TNBC) IFNγ signaling restrains tumor growth in the primary site but promotes it in lung metastasis following treatment. I hypothesize that by studying how IFNγ regulates TNBC’s ability to evade immune cells and establish metastatic lesions, we can better understand the contexts in which IFNγ delivery by immune cells promotes or restrains tumor growth in the metastatic setting. To do so, I propose two aims: Aim 1: Elucidating the role of IFNγ in immune evasion during TNBC dissemination and metastatic growth and Aim 2: Dissecting IFNγ’ s role in establishing the metastatic potential of primary TNBCs. Combined this body of work will extend our knowledge of the endogenous role of IFNγ in the antitumor immune response and how modulating its signaling may play a role in the clinic. Beyond understanding the roles of IFNγ during metastasis, this proposal also seeks to lay the appropriate training groundwork necessary for successfully pursuing an independent faculty position. Through a detailed training plan dedicated to developing both the technical and leadership skills required to successfully lead a laboratory, this work will be used as a springboard for future applications to tenure track positions. Together with the research component, this will form a strong foundation for an independent research program dedicated to understanding how cellular communication effects molecular phenotypes during immune cell interactions with tumor cells.