CD8 T cells must receive optimal signals 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. Within the largely exhausted T cell milieu, rare but important elements of potent anti-tumor reactivity exist. Specifically marking CD8 T cells that display hallmarks of potent activation, we aim to discover and harness the regulatory networks underlying robust anti-tumor function. We hypothesize that these T cells exist in defined niches which instruct their phenotype and function. A spatial and dynamic map of potent effector behavior and niches is a pathway to engineer robust anti-tumor immunity.

Preventing cytotoxic CD8 T cells from accessing the cancer cells is another level at which effective immune regulation of cancer is thwarted. 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 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 shaping anti-tumor immunity.

Complex 3D environments such as a cancer-inflicted epithelial tissue pose unique challenges for cytotoxic T cells in accessing, recognizing and being able to successfully kill cancer cells. We seek to understand what microenvironmental and T cell-specific conditions are necessary for generation and maintenance of potent cytotoxic CD8 T cells in the context of a mechanically complex 3D tumor. Further, we are interested in the dynamic processes of recognition and target cell killing as they occur in structurally complex 3D environments with extracellular matrix scaffolding.