Ferreira Lab
Designing and developing engineered immune cell therapies
for autoimmune disease, cancer, and aging
Mission
The immune system is everywhere in the body. How can we tap into this bodily global positioning system? How can we design immune cells as living drugs? Is it possible to reeducate an immune system? The Ferreira Lab uses engineered immune receptors to systematically study how specificity, affinity, and signaling modulate T cell function in immunity and tolerance. We aim to shed light on the biology of different subsets of T cells and help unleash their potential as cell-based therapies for autoimmune disease, cancer, and aging.
Research
The adaptive immune system has evolved to specifically recognize and destroy a virtually infinite variety of pathogens (non-self), while remaining unresponsive towards tissues (self). A subset of helper T lymphocytes dedicated to suppressing immune responses, regulatory T cells (Tregs) are essential to maintain self tolerance and immune homeostasis. Yet, Tregs also constitute a barrier to anticancer immunity by heavily accumulating in tumors, inhibiting their clearance by tumor antigen-specific T cells.
Manipulating human Tregs offers the opportunity to modulate the immune system with antigen specificity in organ transplant rejection and autoimmunity. In addition, Tregs have the potential to help correct the defects in tissue repair and curb low-grade chronic inflammation observed in degenerative diseases and aging.
Yet, antigen-specific Tregs are vanishingly rare. Moreover, the best antigen target is often unknown. Synthetic biology can be used to impart a desired specificity to human Tregs, greatly expanding what targets can be pursued using Treg-based therapies. Chimeric antigen receptors (CARs) are synthetic immune receptors comprising an extracellular antibody-based antigen-binding domain and an intracellular signaling domain. By combining T cell signal 1 and signal 2 in its endomain, a CAR allows for potent T cell activation directly downstream of antigen recognition.
The CAR platform allows one to systematically study how specificity, affinity, and signaling modulate Treg and effector T cell function. It can also be used to target these cells to specific tissues and disease states independently of endogenous antigens recognized by resident lymphocytes, which have revealed difficult to identify, especially in outbred humans.
The Ferreira Lab uses CARs and other engineered immune receptors to dissect how specificity, affinity, and signaling modulate the function of different T cells subsets in tolerance and immunity, ultimately informing the design and development of new immune cell-based therapies.
Lab members
Selected publications
Cochrane R.W., Fiorentino, A., Allen, E., Robino, R.A., Quiroga, J., Ferreira, L.M.R., 2024. How to test human CAR T cells in solid tumors, the next frontier of CAR T cell therapy. Methods Mol Biol 2748:243-265
Zimmerman, C.M., Robino, R.A., Cochrane R.W., Dominguez, M.D., Ferreira, L.M.R., 2024. Redirecting human conventional and regulatory T cells using chimeric antigen receptors. Methods Mol Biol 2748:201-241
Tennant, M.D., New, C., Ferreira, L.M.R., O’Neil, R.T., 2023. Efficient T cell adoptive transfer in lymphoreplete hosts mediated by transient Stat5 signaling. Mol Ther 31 (9), 2591-2599
Skartsis, N., Muller, Y.D., Ferreira, L.M.R., 2023. Regulatory T cell homeostasis: requisite signals and implications for clinical development of biologics. Clin Immunol 246: 109201
Ghobadinezhad, F., Ebrahimi, N., Mozaffari, F., Moradi, N., Beiranvand, S., Pournazari, M., Rezaei-Tazangi, F., Khorram, R., Afshinpour, M., Robino, R., Aref, A.R., Ferreira, L.M.R., 2022. The emerging role of regulatory cell-based therapy in autoimmune disease. Front Immunol 13:1075813
Khosravi-Maharlooei, M., Madley, R., Borsotti, C., Ferreira, L.M.R., Sharp, R.C., Brehm, M.A., Greiner, D.L., Parent, A.V., Anderson, M.S., Sykes, M., Creusot, R.J., 2022. Modeling human T1D-associated autoimmune processes. Mol Metab 56:101417
Skartsis, N., Peng, Y., Ferreira, L.M.R., Nguyen, V., Ronin, E., Muller, Y.D., Vincenti, F., Tang, Q., 2021. IL-6 and TNFa drive extensive proliferation of human Tregs without compromising their lineage stability or function. Front Immunol 12:783282
Ferreira, L.M.R., Muller, Y.D., 2021. CAR T-cell therapy: is CD28-CAR heterodimerization its Achilles’ heel? Front Immunol 12:766220
Muller, Y.D., Ferreira, L.M.R., Ronin, E., Ho, P., Nguyen, V., Faleo, G., Zhou, Y., Lee, K., Leung, K.K., Skartsis, N., Kaul, A.M., Mulder, A., Claas, F.H.J., Wells, J.A., Bluestone, J.A., Tang, Q., 2021. Precision engineering of an anti-HLA-A2 chimeric antigen receptor in regulatory T cells for transplant immune tolerance. Front Immunol 12:686439
Muller, Y.D., Nguyen, D.P., Ferreira, L.M.R., Ho, P., Raffin, C., Valencia, R.B., Congrave-Wilson, Z., Roth, T., Eyquem, J., Van Gool, F., Marson, A., Perez, L., Wells, J.A., Bluestone, J.A., Tang, Q., 2021. The CD28-transmembrane domain mediates chimeric antigen receptor heterodimerization with CD28. Front Immunol 12:639818
Ferreira, L.M.R., Muller, Y.D., Bluestone, J.A., Tang, Q., 2019. Next-generation regulatory T cell therapy. Nat Rev Drug Discov 18, 749-769
Han, X., Wang, M., Duan, S., Franco, P.J., Kenty, J.H.R., Hedrick, P., Xia, Y., Allen, A., Ferreira, L.M.R., Strominger, J.L., Melton, D.A., Meissner, T.B., Cowan, C.A., 2019. Generation of hypoimmunogenic human pluripotent stem cells. Proc Natl Acad Sci USA 116 (21), 10441-10446
Ferreira, L.M.R., Meissner, T.B., Tilburgs, T., Strominger, J.L, 2017. HLA-G: at the interface of maternal-fetal tolerance. Trends Immunol 38 (4), 272-286
Ferreira, L.M.R., Meissner, T.B., Mikkelsen, T.S., Mallard, W., O’Donnell, C.W., Tilburgs, T., Gomes, H.A.B., Camahort, R., Sherwood, R.I., Gifford, D.K., Rinn, J.L., Cowan, C.A., Strominger, J.L., 2016. A distant trophoblast-specific enhancer controls HLA-G expression at the maternal-fetal interface. Proc Natl Acad Sci USA 113 (19), 5364-5369
Mandal, P.K., Ferreira, L.M.R., Collins R., Meissner T.B., Boutwell C.L., Friesen M., Vrbanac V., Garrison B.S., Stortchevoi A., Bryder D., Musunuru K., Brand H., Tager A.M., Allen T.M., Talkowski M.E., Rossi D.J., Cowan C.A., 2014. Efficient Ablation of Genes in Human Hematopoietic Stem and Effector Cells using CRISPR/Cas9. Cell Stem Cell 15(5), 643-652