Research interest
Combating tumor immune escape and immunotherapy
We aim to identify mechanisms of tumors immune escape and to develop therapeutic protocols to overcome these. Tumor immune escape mechanisms include inhibitory molecules on tumor cells or on antigen presenting cells and immune regulatory cells in the tumor environment. The functional characterization of inhibitory molecules, exploration of their inhibition and the examination of possible synergy with small molecule based targeted therapies may help in designing novel approaches to improve anticancer immunotherapy.
Development of an inducible murine melanoma model
It is crucial to test new therapeutic approaches in appropriate in vivo models that simulate the human cancer reality. Transplantable tumor models often do not mimic the complex interaction between the tumor cell and the tumor microenvironment and therefore may have little predictive value for the treatment of cancer patients. Inducible or spontaneous murine melanoma models are more physiological, but due to the late onset of tumor formation less practical for long-term immunotherapeutic experiments. By crossing mice that inducible express the in human melanoma often observed mutations BRAFV600E and loss of PTEN, we could induce melanoma in these mice at a high penetrance and at short time to onset. We found TIL within the tumor environment and could culture TIL and tumor cell lines, making this model highly valuable for testing small molecule approaches as well as immunotherapeutic approaches.
Role of co-inhibitory molecules during tumor immune escape
Appropriate T cell activation depends on TCR ligation and a positive secondary signal. Recent work revealed that this secondary signal is not an on-off phenomenon but a signal of modulated intensity, which is orchestrated by several co-stimulatory and co-inhibitory molecules. We and others have shown that one of the ligands (PD-L1) of one such a co-inhibitory molecule (PD-1) is highly expressed on tumor cells and leads to impaired immune responses. We found an increased PD-L1 expression on metastases compared to primary melanoma in human, but no influence on overall survival, raising the question in which situations PD-L1 inhibits tumor specific T cells, which is a current project.
Homeostatically proliferating T cells for the treatment of cancer
One approach in immunotherapy is the adoptive transfer of tumor-reactive T cells. For effective tumor growth control, tumor-reactive T cells should sufficiently expand and survive, without exhaustion. Transfer of naïve peripheral T cells into lymphopenic murine recipients results in a slow cytokine-driven proliferation of these T cells. During this homeostatic proliferation (HP), T cells acquire effector functions (IFN-production, lytic activity), while keeping characteristics of naïve T cells. This results in better CD62L-mediated lymph node homing, less anergy induction and better tumor growth control compared to naïve or effector T cells. As induction of lymphopenia by chemo- or chemoradiotherapy is accompanied by serious adverse events we aim at a HP in vitro induction. Recently, we could expand T cells in vitro with superior tumor growth control capabilities in vivo (in mice) and characterize them at the moment in comparison to naïve, primed and memory T cells.
Generation of RCC TIL after tyrosine kinase inhibitor pretreatment
Neoadjuvant treatment of patients has been shown to improve the outcome of surgery and radiotherapy. We are currently exploring such an approach to improve expansion of tumor infiltrating lymphocytes (TIL) from renal cell carcinoma (RCC). TIL therapy is a promising immunotherapeutic approach in melanoma inducing long lasting clinical responses currently tested at several institutes. Culture of TIL generated from RCC has been described before, but failed to induce clinical responses. Reason for this is that former protocols lacked preconditioning of the patients to induce lymphopenia. We are aiming at expanding TIL from pretreated RCC patients to expand higher TIL numbers with more gentle expansion protocols to prevent exhaustion and negative selection.
Key publications
Gadiot Jules, Hooijkaas Anna, Kaiser Andrew, van Tinteren Harm, van Boven Hester, Blank Christian. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011 May 15;117(10):2192-201.
Borkner L, Kaiser A, van de Kasteele W, Andreesen R, Mackensen A, Haanen JB, Schumacher TN, Blank C. RNA interference targeting programmed death receptor-1 improves immune functions of tumor-specific T cells. Cancer Immunol Immunother. 2010 Aug;59(8):1173-83.
Kerstin Schuster, Jules Gadiot, Reinhard Andreesen, Andreas Mackensen, Thomas F. Gajewski, Christian Blank. Homeostatic proliferation of naïve CD8+ T cells depends on CD62L/L-selectin-mediated homing to peripheral LN. Eur J Immunol. 2009 Nov; 39(11):2981-2990
Hadrup SR, Bakker AH, Shu CJ, Andersen RS, van Veluw J, Hombrink P, Castermans E, Thor Straten P, Blank C, Haanen JB, Heemskerk MH, Schumacher TN. Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods. 2009 Jul;6(7):520-6.
Kline J, Brown IE, Zha YY, Blank C, Strickler J, Wouters H, Zhang L, Gajewski TF. Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. Clin Cancer Res. 14 (2008), 3156-3167.
Marcus Mühlbauer, Martin Fleck, Christian Schütz, Thomas Weiss, Matthias Froh, Christian Blank, Jürgen Schölmerich and Claus Hellerbrand. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol. 2006 Oct;45(4):520-8.
Ian E. Brown, Christian Blank, Alok K. Kacha and Thomas F. Gajewski. Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J Immunol 177 (2006), 4521-4529
Christian Blank, Juergen Kuball, Simon Voelkl, Heinz Wiendl, Bernd Becker, Bernhard Walter, Otto Majdic, Thomas F. Gajewski, Mathias Theobald, Reinhard Andreesen and Andreas Mackensen. Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 119 (2006) 317-327
Christian Blank, Mary A. Markiewicz, Ian Brown, and Thomas F. Gajewski. ICAM-1 contributes to but is not essential for tumor antigen cross-priming and CD8+ T cell-mediated tumor rejection in vivo. J Immunol. 174 (2005) 3416-20
Christian Blank, Ian Brown, Amy C. Peterson, Mike Spiotto, Tasuku Honjo, and Thomas F. Gajewski. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 64 (2004), 1140-45
Blank C, Brown I, Marks, R, Nishimura H, Honjo T, Gajewski TF. Absense of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells. J. Immunol 171 (2003), 4574-81
Kwang Woo Hwang, William B. Sweatt, Ian E. Brown, Christian Blank, Thomas F. Gajewski, Jeffrey A. Bluestone, Maria-Luisa Alegre. Targeted Ligation of CTLA-4 In Vivo by Membrane-Bound Anti-CTLA-4 Antibody Prevents Rejection of Allogeneic Cells. J. Immunol. 169 (2002), 633-637
Grayson B. Lipford, Marc Bauer, Christian Blank, Hermann Wagner and Klaus Heeg. CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: a new class of vaccine adjuvants. Eur. J. Immunol. 27 (1997), 2340-2344
Blank, C., Luz, A., Bendigs, S., Erdmann, A., Wagner, H., and Heeg, K. Superantigen and endotoxin synergize in the induction of lethal shock. Eur. J. Immunol. 27 (1997), 825-833
Co-workers
Andrew Kaiser PhD Post-Doc
Anna Hooijkaas MSc PhD student
Aurelie Guislain Technical Staff
Jules Gadiot Technical staff
