Regulation of T cell activity in cancer, infection, and immunotherapies
Leveraging the protective capacity of the immune system to eliminate malignant cells has emerged as an exciting and promising strategy for the treatment of cancer. The overall focus of our lab is to develop new approaches for enhancing the efficacy of cancer immunotherapies. Promising modalities in the immuno-oncology landscape include checkpoint blockade, adoptive cell therapy, cancer vaccines, cytokine therapies, and oncolytic viruses. CD8 T lymphocytes are central mediators of cancer immunity, and as such, nearly all effective immunotherapies elicit tumor regression through promoting robust anti-tumor CD8 T cell responses. However, inhibitory features of the immunosuppressive tumor microenvironment often prevent sustained T-cell activity and efficient elimination of malignant cells, contributing to variable immunotherapy responsiveness and treatment resistance. The primary goal of our research is to delineate the complex signals regulating tumor-specific CD8 T cell fate, heterogeneity, persistence, and function in cancer. We utilize cutting-edge genetic and molecular approaches to identify transcription factors and chromatin modifiers controlling CD8 T-cell differentiation within tumors and ultimately seek to leverage this insight to tailor the activity of T-cells for enhanced immunotherapy success.
Our group also studies the molecular signals controlling CD8 T cell differentiation and function during infection. Memory CD8 T cells are central mediators of long-lived immunity and provide critical protection against intracellular pathogens. Memory CD8 T cells can be broadly segregated into circulating memory cells predominantly found in the blood and lymphoid tissues as well as tissue-resident memory cells, which are primarily localized in non-lymphoid sites. Given the unique attributes of memory T cells, including specificity, durability, and robust cytotoxic potential, leveraging this population of cells is a key objective of many vaccines.
Milner J.J., Toma C., Quon S., Omilusik K., Scharping N.E., Dey A., Reina-Campos M., Nguyen H., Getzler A.J., Diao H., Yu B., Deploux A., Yoshida T., Li D., Qi J., Vincek A., Hedrick S.M., Egawa T., Zhou M., Crotty S., Ozato K., Pipkin M.E., Goldrath A.W. Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation in response to infection and cancer. J Exp Med. 2021; 218(8):e20202512.
Milner J.J.*,#, Nguyen H.*, Omilusik K., Reina-Campos M., Toma C., Delpoux A., Boland B.S., Hedrick S.M., Chang J.T., Goldrath A.W.# Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population. PNAS. 2020; 117(41):25667-25678. *Co-first authors; #Co-corresponding authors.
Milner J.J., Toma C., He Z., Kurd N.S., Nguyen Q.P., McDonald B., Quezada L., Widjaja C.E., Witherden D.A., Crowl J.T., Shaw L.A., Yeo G.W., Chang J.T., Omilusik K.D.*, Goldrath A.W.* Heterogenous populations of tissue-resident CD8 T cells are generated in response to infection and malignancy. Immunity. 2020; 52(5): 808-824.
Milner J.J., Toma C., Yu B., Zhang K., Omilusik K., Phan A.T., Wang D., Getzler A.J., Ngyuen T., Crotty S., Wang W., Pipkin M.E., Goldrath A.W. Runx3 programs CD8 T cell residency in non-lymphoid tissues and tumours. Nature. 2017; 552(7684):253-25