Research Area
As an independent investigator I have applied cutting-edge genome wide and single-cell epigenetic profiling approaches to assessing transcriptional regulation of genes that are critical in the development of functional and exhausted T cells generated in response to acute and chronic viral infections and tumors. My lab continues to investigate fundamental molecular mechanism(s) critical for development of long-lived memory CD4 and CD8 T cell functions. Moreover, my lab has established a robust research program investigating the role of epigenetic modifications in regulating T cell differentiation and how these programs affect the efficacy of T cell-based immunotherapy.
Team Description
Immune cell-based therapies have emerged as a promising new tool in the fight against cancer and chronic infections. Prolonged stimulation of T cells leads to “exhaustion” and limits their ability to function. We use a combination of epigenetic and computational techniques to study this T cell exhaustion. Our laboratory wants to understand the mechanisms that regulate the development of T cells during infection, cancer, and autoimmunity with the goal of improving treatments for these diseases.
Team Members
Team Show
Publications
1. Fonseca R, Beura LK, Quarnstrom CF, Ghoneim HE, Fan Y, Zebley CC, Scott MC, Fares-Frederickson NJ, Wijeyesinghe S, Thompson EA, Borges da Silva H, Vezys V, Youngblood B, Masopust D. Developmental plasticity allow outside-in immune response by resident memory T cells. Nature Immunology 4):412-421 April 2020
2. Abdelsamed HA, Zebley CC, Nguyen H, Rutishauser RL, Fan Y, Ghoneim HE, Crawford JC, Alfei F, Alli S, Ribeiro SP, Castellaw A, McGargill M, Jin H, Boi SK, Speake C, Serti E, Turka LA, Busch ME, Stone M, Deeks SG, Sekaly RP, Zehn D, James EA, Nepom GT, Youngblood B*. Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes. Nature Immunology (5):578-587 May 2020
3. Galletti G., Simone G., Mazza E.M.C., Puccio S., Mezzanotte C., Bi T.M., Davydov A.N., Metsger M., Scamardella W., Alvisi G., Paoli F., Zanon V., Scarpa A., Camisa B., Colombo F.S., Anselmo A., Peano C., Polletti S., Mavilio D., Gattinoni L., Boi S.K., Youngblood B., Jones R.E., Baird D.M., Gostick E., Llewellyn-Lacey S., Ladell K., Price D.A, Chudakov D.M., Newell E.W., Casucci M., and Lugli E. Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans. Nature Immunology 2020 Dec;21(12):1552-1562 2020
4. Verma V., Jafarzadeh N., Boi S.K., Kundu S., Fan Y., Nandre R., Zeng P., Alolaqi F., Ahmad S., Barry S.T., Valge-Archer V., Smith P.D., Banchereau J., Mkrtichyan M., Youngblood B., Rodriguez P.C., Gupta S., Khleif S.N. MEK inhibition reprograms CD8+ T cells into stem cell memory with potent anti-tumor effects by delaying cell division and enhancing metabolic fitness. Nature Immunology 2021 January ;22(1):53-66
5. Huang Q.S., Wood T., Jelley L., Jennings T., Jefferies S., Daniells K., Nesdale A., Dowell T., Turner N., Campbell-Stokes P., Balm M., Dobinson H. C., Grant C.C., James S., Aminisani N., Ralston J., Gunn W., Bocacao J., Danielewicz J., Moncrieff T., McNeill A., Lopez L., Waite B., Kiedrzynski T., Schrader H., Gray R., Cook K., Currin D., Engelbrecht C., Tapurau W., Emmerton L., Martin M., Baker M.G., Taylor S., Trenholme A., Wong C., Lawrence S., McArthur C., Stanley A., Roberts S., Rahnama F., Bennett J., Mansell C., Dilcher M., Werno A., Grant J., van der Linden A., Youngblood B., Thomas P.G. & NPIsImpactOnFlu Consortium* Webby R.J. Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand. Nature Communications 2021 2021 Feb 12;12(1):1001.
6. Zheng W., Wei J., Zebley C., Jones L.L., Dhungana Y., Wang Y.D., Mavuluri J., Long L., Fan Y., Youngblood B., Chi H., Geiger T.L.. Regnase-1 suppresses Tcf-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL. Blood 2021 July:15, 138 (2)
7. Prinzing B., Zebley C., Petersen CT, Fan Y., Anido A.A., Yi Z., Nguyen P., Houke H., Bell M., Haydar D., Brown C., Boi S., Alli S., Crawford J.C., Riberdy J., Park J., Zhou S., Velasquez M.P., DeRenzo C., Lazzarotto C.R., Tsai S.Q., Vogel P., Pruett-Miller S.M., Langfitt D., Gottschalk S., Youngblood B*, and Krenciute G. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances anti-tumor activity. Science Translational Medicine 2021 Nov. 17;13 (620).
8. Zebley C.C., Abdelsamed H.A., Ghoneim H.E., Alli S., Haydar D., Harris T., McGargill M.A., Krenciute G., and Youngblood B*. Proinflammatory cytokines promote TET2-mediated DNA demethylation during CD8 T cell effector differentiation. Cell Reports, 2021, Oct. 12; 37 (2).
9. Zebley C.C., Brown C., Mi T., Fan Y., Alli S., Boi S., Galletti G., Lugli E., Langfitt D., Metais J.Y., Lockey T., Meagher M., Triplett B., Talleur A.C., Gottschalk S., and Youngblood B*. CD19-CAR T cells undergo exhaustion epigenetic programming in patients with acute lymphoblastic leukemia. Cell Reports, 2021, Nov. 30; 37 (9).
10. Moustaki A., Crawford J.C., Alli S., Fan Y., Boi S., Zamora A.E., McDonald N.M.N., Wu G., Nakitandwe J., Newman S., Foy S., Silkov A., Thomas P.G., Pappo A., Dyer M.A., Stewart E., Federico S., Youngblood B*. Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation. Science Immunology. 2022 Feb. 4; 7 (68).
11. Baer M.R., Kogan A. A., Bentzen S. M., Mi T., Lapidus R. G., Duong V.H., Emadi A., Niyongere s., O'Connell C. L., Youngblood B.A., Baylin S. B., Rassool F. V. Phase I clinical trial of DNA methyltransferase inhibitor decitabine and PARP inhibitor talazoparib combination therapy in relapsed/refractory acute myeloid leukemia. Clinical Cancer Research. 2022 Apr 1;28(7):1313-1322
12. Talleur A.C., Qudiemat A., Metais JY, Langfitt D., Mamcarz E., Crawford J.C., Huang S., Cheng C., Hurley C., Madden R., Sharma A., Suliman A., Srinivasan A., Velasquez P., Obeng E., Willis C., Akel S., Karol S.E., Inaba H., Bragg A., Zheng W., Zhou S., Schell S., Tuggle-Brown M., Cullins D., Patil S.L., Li Y., Thomas P.G., Zebley C., Youngblood B., Pui C.H, Lockey T., Geiger T.L., Meagher M., Triplett B.M., and Gottschalk S. Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric BALL. Blood Advances Nov 8;6(21):5737-5749.
13. O'Connell C.L., Baer M.R., Ørskov A.D., Saini S.K., Duong V.H., Kropf P., Hansen J.W., Tsao-Wei D., Jang H.S., Emadi A., Holmberg-Thyden S., Cowland J., Brinker B.T., Horwood K., Burgos R., Hostetter G., Youngblood B., Hadrup S.R., Issa J.P., Jones P., Baylin S.B., Siddiqi I., Grønbæk K.. Safety, outcomes and T cell characteristics in patients with relapsed or refractory MDS or CMML treated with atezolizumab in combination with guadecitabine. Clinical Cancer Research. 2022 Oct. 12
14. Soerens A.G., Künzli M., Quarnstrom C.F., Scott M.C., Swanson L., Locquiao J.J., Zehn D., Youngblood B., Vezys V., Masopust D. Functional T cells are capable of supernumerary cell division and longevity. Nature 2023 Feb;614(7949):762-766.