Dr. Holderried and his group focus on cellular immunoregulatory mechanisms and their role in steady state and disease. Of particular interest is the recently identified Qa-1 (HLA-E in man) restricted CD8+ regulatory T cell population (Treg), its impact on anti-tumor immune response and in Graft-versus-Host Disease (GvHD) following allogeneic stem-cell transplantation. The interactions of CD8+ Treg with other immune cells, notably additional regulatory cell subpopulations, play a major part in these analyses.
Immunosuppresion in the tumor-microenvironment induced by regulatory T cells has been shown to have a major impact on tumor behavior by allowing tumor escape, impairing the anti-tumor response in patients and constricting the success of immunotherapeutic options. In patients with Graft-versus-Host Disease Treg have shown in clinical trials to be an effective addition to current treatment regimens. The majority of studies addressing this issue, both in mice and humans, have focused on CD25+FOXP3+CD4+ regulatory T cells, which have led to many groundbreaking discoveries. However, the contribution of cellular mechanisms involved in regulatory CD8+ T cell-mediated immune responses has not been appreciated until recently.
Dr. Holderried’s group aims to further analyze the character of the cancer regulatory mechanisms of murine CD8+ Treg and their role in GvHD development and treatment. This knowledge is being used to identify the human homologue of the murine CD8+ Treg subpopulation. Close collaborations within the University Hospital allow translational assessment of human CD8+ Treg in malignant disease and during immune reconstitution after allogeneic stem-cell transplantation. The insights of this work should help to elucidate cellular immunoregulatory mechanisms by human CD8+ Treg and might lead to new immunotherapeutic approaches.
Education / Training
Institution and Location/Major/Degree, Year/
University of Bonn, Germany / Internal Medicine, Hematology, Oncology / Residency, since 2008
University of Tübingen, Germany / Clinical Immunology / MD thesis, 2011
University of Freiburg, Germany / Medicine / Medical license, 2007
University of Tübingen, Germany / Medicine / Medical license, 2007
University of Cape Town, South Africa / Medicine / Medical license, 2007
Queen Mary University of London, UK / Medicine / Medical license, 2007
Harvard Medical School, Boston, USA / Medicine / Medical license, 2007
University of Michigan, Ann Arbor, USA / Medicine / Medical license, 2007
Appointments / Positions Held
Year/Position/Institution
since 2008 / Resident in the Medical Clinic III for Oncology, Hematology and Rheumatology /
University of Bonn, Germany
since 2016 / Group leader of a BONFOR junior research group, Institute of Experimental Immunology / University of Bonn, Germany
2011 – 2013 / Postdoctoral fellow, Dana-Farber Cancer Insitute PI: Harvey Cantor / Harvard Medical School, USA
2004 – 2005 / Research Associate, Dana-Farber Cancer Insitute PI: John G. Gribben / Harvard Medical School, USA
Honors / Awards
2011 Carl-Liebermeister Award, Eberhard Karls University Tübingen
2004 Travel Award, American Society of Hematology
2003 – 2007 Scholarship, the Konrad-Adenauer-Foundation
Memberships
German Society of Hematology and Oncology (DGHO)
European Society of Hematology (EHA)
American Society of Clinical Oncology (ASCO)
Publications
1. Long-term survival correlates with immunological responses in renal cell carcinoma patients treated with mRNA-based immunotherapy. Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, Horger MS, Maksimovic O, Stenzl A, Hoerr I, Rammensee HG, Holderried TAW, Kanz L, Pascolo S, Brossart P. Oncoimmunology. in press.
2. Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, Kaygusuz Y, Meissner T, Holderried TAW, Chan S, Kastner P, Haining WN, Cantor H. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science. 2015 Oct 16;350(6258):334-9.
3. Hilgendorf I, Theurl I, Gerhardt LMS, Robbins CS, Weber GF, Gonen A, Iwamoto Y, Degousee N, Holderried TAW, Winter C, Shvartz E, Zirlik A, Lin HY, Sukhova GK, Butany J, Rubin BB, Witztum JL, Libby P, Nahrendorf M, Weissleder R, Swirski FK. Innate response activator B cells aggravate atherosclerosis by stimulating TH1 adaptive immunity. Circulation. 2014; 129:1677-87
4. Hilgendorf I, Gerhardt LMS, Tan T, Winter C, Holderried TAW, Chousterman BG, Iwamoto Y, Liao R, Zirlik A, Scherer-Crosbie M, Hedrick, Libby P, Nahrendorf M, Weissleder R, Swirski FK. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res. 2014; 114:1611-22
5. Alvarez-Arias DA, Kim HJ, Zhou P, Holderried TAW, Wang X, Dranoff D, Cantor H. Disruption of CD8+ Treg activity results in expansion of T follicular helper cells and enhanced antitumor immunity. Cancer Immunol Res. 2014; 2:207-216
6. Holderried TAW, Lang PA, Kim HJ, Cantor H. Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection. Proc Natl Acad Sci U S A. 2013; 52:21089-94.
7. Heine A, Held SA, Bringmann A, Holderried TAW, Brossart P. Immunomodulatory effects of anti-angiogenic drugs. Leukemia. 2011; 6:899-905. Review
8. Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, Horger MS, Maksimovic O, Stenzl A, Hoerr I, Rammensee HG, Holderried TAW, Kanz L, Pascolo S, Brossart P. Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol Ther. 2011; 19:990-9.
9. Heine A, Holderried TAW, Brossart P. Tumorvakzinierung beim metastasierten Nierenzellkarzinom. Onkopipeline. 2010; 3:4-10. Review
10. Knödler A, Schmidt SM, Bringmann A, Weck MM, Brauer KM, Holderried TAW, Heine AK, Grünebach F, Brossart P. Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells. Leukemia 2009; 23:535-44.
11. Görgün G*, Ramsay AG*, Holderried TAW*, Zahrieh D, Le Dieu R, Liu F, Quackenbush J, Croce CM, Gribben JG. Eµ-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. Proc Natl Acad Sci U S A. 2009; 106:6250-5.
12. Heine A, Holderried TAW, Brossart P. Immunotherapy in renal cell carcinoma. Immunotherapy, 2009; 1:97-107. Review
13. Schmidt SM, König T, Bringmann A, Held S, von Schwarzenberg K, Heine A, Holderried TAW, Stevanovic S, Grünebach F, Brossart P. Characterization of BAX inhibitor-1 as a novel leukemia-associated antigen. Leukemia. 2009; 25:1818-24.
14. Heine A, Grünebach F, Holderried T, Appel S, Weck MM, Dörfel D, Sinziger C, Brossart P. Transfection of dendritic cells with in vitro-transcribed CMV RNA induces polyclonal CD8+- and CD4+-mediated CMV-specific T cell responses. Mol Ther. 2006; 13:280-8.
15. Görgün G, Holderried TAW, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest, 2005; 115:1797-805.