Dana-Farber Cancer Institute Professor
Department of Immunology, HMS
We study the molecular pathways that regulate T cell function in the tumor microenvironment, with an emphasis on developing novel mechanistic insights that lead to the development of the next generation of cancer immunotherapies. We integrate analysis of human tumor specimens to discover novel pathways and then use experimental mouse models to define their function. Using this approach, we have discovered novel therapeutic targets, including the CD161 inhibitory receptor that is highly upregulated by human tumor-infiltrating T cells. This receptor binds to CLEC2D which is upregulated on tumor cells and immunosuppressive myeloid cells in the microenvironment (Mathewson et al, Cell 2021). We also use genetic screens to discover key regulators of T cell – tumor cell interactions. This approach led to the discovery of the epigenetic enzyme CARM1 as a target for cancer immunotherapy. We found that inactivation of CARM1 in T cells reduced T cell exhaustion, while inhibition of CARM1 in tumor cells induced a type 1 interferon program that promoted T cell-mediated immunity (Kumar et al, Cancer Discovery 2021).
We also study immune evasion mechanisms by cancer cells. DNA damage pathways result in upregulation of cellular stress molecules, including the MICA and MICB ligands for the activating NKG2D pathway expressed by NK cells and CD8 T cells. Tumor cells evade this immune recognition pathway by proteolytic shedding of MICA/B. We have developed a monoclonal antibody that inhibits proteolytic MICA/B shedding and thereby sensitizes tumor cells to killing by NK cells (de Andrade et al, Science 2018). We have also developed a cancer vaccine against the MICA/B domain targeted by the shedding enzymes. This vaccine induces a coordinated T cell and NK cell response against tumors and remains active against tumor cells resistant to CD8 T cells. In such MHC-I deficient tumors, CD4 T cells recruit NK cells which then serve as the major effector cells (Badrinath et al, Nature 2022).
- are using high-dimensional imaging techniques to define immune cell - tumor cell interactions in human tumors and murine models. In these studies, we combine CODEX imaging with spatial transcriptomics. We are particularly interested in genes expressed by tumor cells that inhibit T cell infiltration and the interaction of T cells with tumor cells and dendritic cells. We have recently discovered that tissue-resident memory T cells are early responders to immune checkpoint inhibition in human tumors (Luoma et al, Cell 2022), and are studying the molecular signals that enable differentiation of T cells into a tissue-resident memory state.
1 Jimmy Fund Way
Smith Building, Room 736A
Boston, MA 02115