People

Academic Titles

Assistant Professor (Incoming)

Research Topic

Microenvironmental regulation of CD8 T cell function in tumors

 

Immunotherapy has revolutionized the treatment of cancer. Most modalities of cancer immunotherapy work by enabling cytotoxic CD8 T cells to recognize and kill cancer cells. These cells, however, do not work in isolation and are inextricably shaped by the aberrant tumor microenvironment (TME), which includes other immune cells such as macrophages and dendritic cells, as well as acellular components such as the extracellular matrix (ECM). We seek to understand the intrinsic and microenvironmental regulation of cytotoxic CD8 T cell function in the context of tumors. We take advantage of novel genetically engineered mouse models to mark specific states of T cells and macrophages, high dimensional immune profiling, live imaging, in vitro 3D ECM culture systems and a variety of other techniques.

CD8 T cells must receive optimal signals from antigen-presenting cells, such as macrophages and dendritic cells to transform into potent effector cells capable of killing target cells. In tumors, this process is misdirected, leading to a dominant differentiation towards T cell exhaustion or dysfunction. We seek to understand what microenvironmental and T cell-specific conditions are necessary for generation of potent cytotoxic CD8 T cells in the context of a mechanically complex 3D tumor, and how the processes of recognition and target cell killing may be impaired by a hostile TME.

Preventing cytotoxic CD8 T cells from accessing the cancer cells is another level at which effective immune regulation of cancer is thwarted. The TME is crucial in this complex process, and one of the key players in the organization of the tumor immune microenvironment are macrophages. The emerging consensus from single cell profiling and functional studies lead to a shift away from the M1/M2 paradigm onto alternative and granular definitions of tumor-associated macrophage (TAM) phenotype. TAMs are important for the infiltration of T cells and organization of T cell-centric modules of anti-tumor immunity in tumors, yet these cells – especially those at the collagen-rich tumor margins – are also implicated in T cell exclusion and exhaustion. We seek to define the context-dependent role of macrophages in the organization of the tumor immune microenvironment.

Our studies extensively use mouse models of cancer, with a view to validate and apply findings in translational settings of human cancer. Advances in our goals are directly linked to enhancing the efficacy of current paradigms and leading to the new discoveries in cancer immunotherapy.