Publications by authors named "Kathleen Anders"

8 Publications

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The immune system prevents recurrence of transplanted but not autochthonous antigenic tumors after oncogene inactivation therapy.

Int J Cancer 2017 12 31;141(12):2551-2561. Epub 2017 Aug 31.

Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

Targeted oncogene inactivation by small molecule inhibitors can be very effective but tumor recurrence is a frequent problem in the clinic. Therapy by inactivation of the cancer-driving oncogene in transplanted tumors was shown to be augmented in the presence of T cells. However, these experiments did not take into account the long-term, usually tolerogenic, interaction of de novo malignancies with the immune system. Here, we employed mice, in which SV40 large T (Tag) and firefly luciferase (Luc) as fusion protein (TagLuc) could be regulated with the Tet-on system and upon activation resulted in tumors after a long latency. TagLuc inactivation induced profound tumor regression, demonstrating sustained oncogene addiction. While tumor relapse after TagLuc inactivation was prevented in immunocompetent mice bearing transplanted tumors, autochthonous tumors relapsed or recurred after therapy discontinuation indicating that the immune system that coevolved with the malignancy over an extended period of time lost the potency to mount an efficient anti-tumor immune response. By contrast, adoptively transferred CD8 T cells targeting the cancer-driving oncogene eradicated recurrent autochthonous tumors, highlighting a suitable therapy option in a clinically relevant model.
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http://dx.doi.org/10.1002/ijc.31009DOI Listing
December 2017

Preventing tumor escape by targeting a post-proteasomal trimming independent epitope.

J Exp Med 2016 10 3;213(11):2333-2348. Epub 2016 Oct 3.

Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany

Adoptive T cell therapy (ATT) can achieve regression of large tumors in mice and humans; however, tumors frequently recur. High target peptide-major histocompatibility complex-I (pMHC) affinity and T cell receptor (TCR)-pMHC affinity are thought to be critical to preventing relapse. Here, we show that targeting two epitopes of the same antigen in the same cancer cells via monospecific T cells, which have similar pMHC and pMHC-TCR affinity, results in eradication of large, established tumors when targeting the apparently subdominant but not the dominant epitope. Only the escape but not the rejection epitope required postproteasomal trimming, which was regulated by IFN-γ, allowing IFN-γ-unresponsive cancer variants to evade. The data describe a novel immune escape mechanism and better define suitable target epitopes for ATT.
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http://dx.doi.org/10.1084/jem.20160636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068242PMC
October 2016

Fas expression by tumor stroma is required for cancer eradication.

Proc Natl Acad Sci U S A 2013 Feb 22;110(6):2276-81. Epub 2013 Jan 22.

Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.

The contribution of molecules such as perforin, IFN-γ (IFNγ), and particularly Fas ligand (FasL) by transferred CD8(+) effector T (T(E)) cells to rejection of large, established tumors is incompletely understood. Efficient attack against large tumors carrying a surrogate tumor antigen (mimicking a "passenger" mutation) by T(E) cells requires action of IFNγ on tumor stroma cells to avoid selection of antigen-loss variants. Because "cancer-driving" antigens (CDAs) are rarely counterselected, IFNγ may be expected to be dispensable in elimination of cancers by targeting a CDA. Here, initial regression of large, established tumors required neither IFNγ, FasL, nor perforin by transferred CD8(+) T(E) cells targeting Simian Virus (SV) 40 large T as CDA. However, cytotoxic T(E) cells lacking IFNγ or FasL could not prevent relapse despite retention of the rejection antigen by the cancer cells. Complete tumor rejection required IFNγ-regulated Fas by the tumor stroma. Therefore, T(E) cells lacking IFNγ or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down-regulated.
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http://dx.doi.org/10.1073/pnas.1218295110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568383PMC
February 2013

Molecular pathways: comparing the effects of drugs and T cells to effectively target oncogenes.

Clin Cancer Res 2013 Jan 29;19(2):320-6. Epub 2012 Nov 29.

Max-Delbrück Center for Molecular Medicine, Robert-Rössle Strasse 10, Berlin, Germany.

Mutant cancer-driving oncogenes are the best therapeutic targets, both with drugs like small-molecule inhibitors (SMI) and adoptive T-cell therapy (ATT), the most effective form of immunotherapy. Cancer cell survival often depends on oncogenes, which implies that they are homogeneously expressed by all cancer cells and are difficult to select against. Mutant oncogene-directed therapy is relatively selective, as it targets preferentially the oncogene-expressing cancer cells. Both SMI and ATT can be highly effective in relevant preclinical models as well as selected clinical situations, and both share the risk of therapy resistance, facilitated by the frequent genetic instability of cancer cells. Recently, both therapies were compared in the same experimental model targeting the same oncogene. It showed that the oncogene-inactivating drug selected resistant clones, leading eventually to tumor relapse, whereas ATT eradicated large established tumors completely. The mode of tumor destruction likely explained the different outcome with only ATT destroying the tumor vasculature. Elucidating the cellular and molecular mechanisms responsible for tumor regression and relapse will define optimal conditions for the clinic. We argue that the ideal conditions of ATT in the experimental cancer model can be translated to individuals with cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3017DOI Listing
January 2013

Oncogene-targeting T cells reject large tumors while oncogene inactivation selects escape variants in mouse models of cancer.

Cancer Cell 2011 Dec;20(6):755-67

Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

The genetic instability of cancer cells frequently causes drug resistance. We established mouse cancer models, which allowed targeting of an oncogene by drug-mediated inactivation or monospecific CD8(+) effector T (T(E)) cells. Drug treatment of genetically unstable large tumors was effective but selected resistant clones in the long term. In contrast, T(E) cells completely rejected large tumors (≥500 mm(3)), if the target antigen was cancer-driving and expressed in sufficient amounts. Although drug-mediated oncogene inactivation selectively killed the cancer cells and left the tumor vasculature intact, which likely facilitated survival and growth of resistant clones, T(E) cell treatment led to blood vessel destruction and probably "bystander" elimination of escape variants, which did not require antigen cross-presentation by stromal cells.
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http://dx.doi.org/10.1016/j.ccr.2011.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658305PMC
December 2011

Depot formation of doxycycline impairs Tet-regulated gene expression in vivo.

Transgenic Res 2012 Oct 14;21(5):1099-107. Epub 2011 Dec 14.

Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.

The tetracycline (Tet) system is widely used for regulation of gene expression in vitro and in vivo. We constructed C57BL/6 transgenic mice (rtTA-CM2) with strong and ubiquitous reverse transactivator (rtTA2(S)-M2) gene expression. rtTA-CM2 mice were crossed to Tet-responsive reporter mice (LC-1) conditionally expressing the firefly luciferase (FLuc) gene under control of a Tet-responsive element, which allowed sensitive quantification of the transactivator activity by bioluminescent imaging. Following doxycycline (dox) application, up to 10(5)-fold increase in BL signal was measured. rtTA activity was inducible in most analyzed organs. After dox withdrawal the BL signal decreased significantly but did not disappear completely, most likely due to a dox depot formation in vivo. The residual dox was sufficient to partly down-regulate a Tet-off controlled oncogene in a tumor transplantation experiment, resulting in reduced tumor growth. rtTA-CM2 mice may be a useful tool to analyze the function of genes in various organs but also reveal that down-regulation of gene expression is not complete.
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http://dx.doi.org/10.1007/s11248-011-9580-0DOI Listing
October 2012

In vivo imaging of an inducible oncogenic tumor antigen visualizes tumor progression and predicts CTL tolerance.

J Immunol 2010 Mar 8;184(6):2930-8. Epub 2010 Feb 8.

Institute of Immunology, Charité Campus Benjamin Franklin, Berlin, Germany.

Visualizing oncogene/tumor Ag expression by noninvasive imaging is of great interest for understanding processes of tumor development and therapy. We established transgenic (Tg) mice conditionally expressing a fusion protein of the SV40 large T Ag and luciferase (TagLuc) that allows monitoring of oncogene/tumor Ag expression by bioluminescent imaging upon Cre recombinase-mediated activation. Independent of Cre-mediated recombination, the TagLuc gene was expressed at low levels in different tissues, probably due to the leakiness of the stop cassette. The level of spontaneous TagLuc expression, detected by bioluminescent imaging, varied between the different Tg lines, depended on the nature of the Tg expression cassette, and correlated with Tag-specific CTL tolerance. Following liver-specific Cre-loxP site-mediated excision of the stop cassette that separated the promoter from the TagLuc fusion gene, hepatocellular carcinoma development was visualized. The ubiquitous low level TagLuc expression caused the failure of transferred effector T cells to reject Tag-expressing tumors rather than causing graft-versus-host disease. This model may be useful to study different levels of tolerance, monitor tumor development at an early stage, and rapidly visualize the efficacy of therapeutic intervention versus potential side effects of low-level Ag expression in normal tissues.
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http://dx.doi.org/10.4049/jimmunol.0900893DOI Listing
March 2010