We are interested in the mechanisms governing antigen cross-presentation and cytotoxic T cell induction in the context of anti-tumor and anti-viral immune responses. Effective cancer vaccines should not only induce strong and durable T cell responses, but also optimally modulate the balance between suppressive and stimulatory factors in the tumor microenvironment. The aim of our research is the identification of novel immunotherapeutic strategies that accomplish both, with a special focus on different pathways of dendritic cell licensing and chemokine receptor modulation.
We further focus on monitoring immune responses aswell as immunomodulatory effects of novel anti-cancer drugs in cancer patients as a means to improve the understanding of basic mechanisms by which cells of the immune system respond to tumors and the ensuing therapy.
The long-term goal is to understand the molecular and cellular regulatory mechanisms in tumor-immune cell interactions and translate basic research investigations into effective cancer immunotherapies.
Ongoing research projects:
1.) Identifying specific chemokine-inducing adjuvants to improve vaccines against viral infections
Whenever an infection occurs, innate effector cells are the first immune cells to combat the microbes, followed by cytotoxic CD8+ T Cells (CTL) after some days. These CTL specifically destroy virally infected cells before neutralizing antibodies become available after some weeks. Such CTL responses against infections must be induced within a few days, should be robust, effective and induce a long-term memory response. In this project, we aim to improve immunotherapeutic vaccination approaches by combining distinct chemokine-inducing adjuvants in different viral models and identify the underlying molecular mechanisms. This project is executed as a close collaboration with Prof. Dr. C. Kurts, Institute of Experimental Immunology, Bonn.
2.) Combining different adjuvants to improve vaccines against tumors
We have shown previously that combining an antigen with different adjuvants results in synergistically enhanced CD8+ T cell responses, by mechanisms involving signal 1, 2 and 3, but also different chemokine receptors. These findings provide a promising approach of novel quality for designing better vaccines against tumors. In this project, we aim to improve immunotherapeutic vaccination approaches in different murine tumor models, with a special focus on chemokines (cooperation with Prof. Kurts), myeloid-derived suppressor cells (cooperation with Dr. Bastian Höchst) aswell as on checkpoint inhibitors.
3.) Identifying the role of NKT-cell-mediated DC-licensing in a model of acute graft-versus-host disease.
Graft-versus-host disease (GVHD) is still one of the most serious and challenging complications after allogeneic hematopoetic stem-cell transplantation. CTL are crucial for causing GVHD. These alloreactive donor T cells secrete large amounts of pro-inflammatory Th1-biased cytokines, which results in further T cell activation and expansion. Chemokines and its receptors are likely to play a role in this complex network. In this project, together with Prof. Dominik Wolf´s group, we aim to identify the role of NKT-cell-mediated, CCR4-dependent DC licensing in a model of acute graft-versus-host disease.
4.) Analysis of immunomodulatory effects of novel anti-cancer drugs
We further focus on monitoring immune responses aswell as immunomodulatory effects – especially on dendritic cells- of novel anti-cancer drugs in cancer patients as a means to improve the understanding of basic mechanisms by which cells of the immune system respond to tumors and the ensuing therapy. This project is executed in close collaboration with Prof. Dr. P. Brossart´s group.
* Excellence Cluster “Immunosensation”
* Bonfor Forschungsförderung
Chrystel Flores, technician
Dr. Sebastian Schlaweck, postdoc
Lisa Charlotte Norkus, phD student
Mareike Held, master student
Christiane Braun, MD student
Leon Strauss, MD student
Caroline Köhler, MD student
Prof. Dr. P. Brossart´s lab and Dr. rer. nat. Stefanie Held
Prof. Dr. C. Kurts, Bonn, Germany
Dr. B. Höchst, Munich, Germany
Prof. Dr. D. Wolf, Bonn, Germany
Dr. Tobias Holderried, Bonn, Germany
PD Dr. Georg Feldmann, Bonn, Germany
The induction of human myeloid-derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Heine A, Schilling J, Grünwald B, Krüger A, Gevensleben H, Held SAE, Garbi N, Kurts C, Brossart P, Knolle P, Diehl L and Höchst B. Cancer Immunol Immunother, 2015, in press
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 TA, Kanz L, Pascolo S, Brossart P. Oncoimmunology, in press.
Interferon gamma modulates sensitivity of CML cells to tyrosine kinase inhibitors. Held SAE*, Heine A* (contributed equally), Kesper AR, Beckers A, Wolf D, Brossart P. Oncoimmunology, in press.
The VEGF-receptor inhibitor axitinib impairs dendritic cell phenotype and function. Heine A, Held SAE, Daecke SN, Riethausen K, Flores C, Kurts C and Brossart P. PlosOne, 2015 Jun 4;10(6):e0128897.
Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Heine A, Brossart P, Wolf D. Blood. 2013 Nov 28;122(23):3843-4.
The JAK-inhibitor Ruxolitinib impairs dendritic cell function in vitro and in vivo. Heine A, Held SAE, Daecke SN, Wallner S, Yajnanarayana SM, Kurts C, Wolf D and Brossart P. Blood. 2013 Aug 15;122(7):1192-202.
Imatinib mesylate and nilotinib affect MHC-class I presentation by modulating the proteasomal processing of antigenic peptides. Held SAE, Duchardt KM, Tenzer S, Rückrich T, von Schwarzenberg K, Bringmann A, Schild HJ, Driessen C, Brossart P and Heine A. Cancer Immunol Immunother. 2012 Nov 25.
Transfection of dendritic cells with in vitro-transcribed CMV RNA induces polyclonal CD8+- and CD4+-mediated CMV-specific T cell responses. Heine A, Grünebach F, Holderried T, Appel S, Weck MM, Dörfel D, Sinzger C, Brossart P. Mol Ther. 2006 Feb;13(2):280-8.