Arnold Han, M.D., Ph.D.
Our research investigates the function of T cells as they pertain to human diseases, including cancer and autoimmunity.
We have recently developed technology than enables determination of T-cell antigen receptor (TCR) sequence and high-dimensional (> 30 parameters) functional phenotype with high accuracy and efficiency from single T cells. Pairing TCR sequence information with high-dimensional phenotypic analysis is particularly powerful in the analysis of T cells, which are exceptionally diverse. In addition to the theoretical TCR repertoire diversity of 1015, T cells can assume diverse pro-inflammatory and regulatory functions. Our approach enables the extensive study of T cell function and also the ability to recapitulate TCRs for functional studies and therapeutic application.
We now understand that T cells are fundamentally capable of recognizing and rejecting tumors as foreign tissue, and tumors grow because they have devised mechanisms of escaping T cell immunity. Recently, therapies specifically designed to incite anti-tumor T cell activity have shown enormous promise in cancer treatment. Our research investigates the function of T cells in human cancer and in mouse models with ultimate aim of identifying novel avenues of therapy. We are addressing the following questions:
1. Of the diverse types of T cells present in tumors, which T cells have potential in controlling cancer and which T cells might actually be promoting cancer growth?
2. How does the TCR repertoire of tumor infiltrating T cells compare with peripheral blood and normal tissue?
3. How do tumor-infiltrating T cells evolve over time?
4. What are the antigens driving tumor-infiltrating T cells?
5. How does immunotherapy affect the landscape and function of T cells, and what are T cell determinants of responsiveness to immunotherapy?
6. Can we apply our technology to design effective strategies for adoptive T cell immunotherapy?
Like cancer, autoimmune diseases are also diseases of T cell tolerance. Our laboratory studies celiac disease, a highly prevalent autoimmune disease of the intestine that shares genetic and immunologic features with many other autoimmune diseases. Aside from its clinical impact, celiac disease is unique among autoimmune diseases in that the triggering antigen, dietary gluten, is known and its exposure can be controlled through diet. Thus, celiac disease provides a unique opportunity to study and understand human autoimmunity. We are investigating T cell responses within celiac disease through the study of blood and tissue from human volunteers. We have previously shown that CD8+ T cells in celiac disease, which mediate tissue damage, are likely responding to gluten ingestion in an antigen-specific manner, even though CD8+ T cells are not believed to directly recognize gluten peptides. Our research on celiac disease is focused on understanding how a CD4+ T cell response directed against an external antigen (dietary gluten) can enable self-tissue damage by CD8+ T cells.
- Gee, M.H.*, Han, A.*, Lofgren, S.M., Beausang, J.F., Mendoza, J.L., Birnbaum, M.E., Bethune, M.T., Fischer, S., Yang, X., Gomez-Eerland, R., Bingham, D.B., Sibener, L.V., Fernandes, R.A., Velasco, A., Baltimore, D., Schumacher, T.N., Khatri, P., Quake, S.R. and Davis, M.M. (2017) Antigen identification for orphan T cell receptors expressed on tumor-infiltrating lymphocytes. Cell pii: S0092-8674(17)31433-2. doi: 10.1016/j.cell.2017.11.043. *equal contribution [Epub ahead of print]
- Hansmann, L., Han, A., Penter, L., Liedtke, M. and Davis, M.M. (2017) Clonal expansion and interrelatedness of distinct B-lineage compartments in multiple myeloma bone marrow. Cancer Immunol Res. 5: 744-754.
- Yan, K.S., Gevaert, O., Zheng, G.X.Y., Anchang, B., Probert, C.S., Larkin, K.A., Davies, P.S., Cheng, Z.F., Kaddis, J.S., Han, A., Roelf, K., Calderon, R.I., Cynn, E., Hu, X., Mandleywala, K., Wilhelmy, J., Grimes, S.M., Corney, D.C., Boutet, S.C., Terry, J.M., Belgrader, P., Ziraldo, S.B., Mikkelsen, T.S., Wang, F., von Furstenberg, R.J., Smith, N.R., Chandrakesan, P., May, R., Chrissy, M.A.S., Jain, R., Cartwright, C.A., Niland, J.C., Hong, Y.K., Carrington, J., Breault, D.T., Epstein, J., Houchen, C.W., Lynch, J.P., Martin, M.G., Plevritis, S.K., Curtis, C., Ji, H.P., Li, L., Henning, S.J., Wong, M.H. and Kuo, C.J. (2017) Intestinal enteroendocrine lineage cells possess homeostatic and injury-inducible stem cell activity. Cell Stem Cell. 21: 78-90.
- Glanville, J., Huang, H., Nau, A., Hatton, O., Wagar, L.E., Rubelt, F., Ji, X., Han, A., Krams, S.M., Pettus, C., Haas, N., Arlehamn, C.S.L., Sette, A., Boyd, S.D., Scriba, T.J., Martinez, O.M. and Davis, M.M. (2017) Identifying specificity groups in the T cell receptor repertoire. Nature 547: 94-98.
- Yan, K.S., Janda, C.Y., Chang, J., Zheng, G.X.Y., Larkin, K.A., Luca, V.C., Chia, L.A., Mah, A.T., Han, A., Terry, J.M., Ootani, A., Roelf, K., Lee, M., Yuan, J., Li, X., Bolen, C.R., Wilhelmy, J., Davies, P.S., Ueno, H., von Furstenberg, R.J., Belgrader, P., Ziraldo, S.B., Ordonez, H., Henning, S.J., Wong, M.H., Snyder, M.P., Weissman, I.L., Hsueh, A.J., Mikkelsen, T.S., Garcia, K.C. and Kuo, C.J. (2017) Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 545: 238-242.
- Han, A., Glanville, J., Hansmann, L. and Davis, M.M. (2105) Corrigendum: Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nature Biotechnol. 33: 210.
- Wei, Y.L., Han, A., Glanville, J., Fang, F., Zuniga, L.A., Lee, J.S., Cua, D.J. and Chien, Y.H. (2015) A highly focused antigen receptor repertoire characterizes gamma delta T cells that are poised to make IL-17 rapidly in naive animals. Frontiers in Immunology 6: 118.
- Han, A., Glanville, J., Hansmann, L. and Davis, M.M. (2104) Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nature Biotechnology 32: 684-692.
- Han, A., Newell, E.W., Glanville, J., Fernandez-Becker, N., Khosla, C., Chien, Y.H. and Davis, M.M. (2013) Dietary gluten triggers concomitant activation of CD4+ and CD8+ alpha beta T cells and gamma delta T cells in celiac disease. Proc. Natl. Acad. Sci. U.S.A. 110: 13073-13078.
- Su, L.F., Kidd, B.A., Han, A., Kotzin, J.J. and Davis, M.M. (2013) Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 38: 373-383.
- Su, L.F., Han, A., McGuire, H.M., Furman, D., Newell, E.W. and Davis, M.M. (2013) The promised land of human immunology. Cold Spring Harbor Symp. on Quant. Bio. 78: 203-213.
- Yan, K.S., Yan, S., Farooq, A., Han, A., Zeng, L. and Zhou, M.M. (2003) Structure and conserved RNA binding of the PAZ domain. Nature 426: 468-474.
- Han, A., Saijo, K., Mecklenbräuker, I., Tarakhovsky, A. and Nussenzweig, M.C. (2003) Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival. Immunity 19: 621-632.