Activated tumor specific cytotoxic T cells (red) attack human tumor cells (not labelled). The attack does not lead to tumor cell destruction but instead to tumor cell division. Cell death is indicated by green colour.

The Interventional Immunology Division investigates cellular and molecular mechanisms by which tumors can protect themselves from immune attack, and develops new approaches for tumor immunotherapy on this basis. The division focuses on three closely linked fields of research:

01 | Immune resistance mechanisms in tumor cells

In this field, the team study the molecular communication between killer T cells and tumor cells to discover the conditions in which an immune attack can destroy tumor cells, and why this is frequently unsuccessful. We use genome-wide screening methods to systematically identify the genes that tumor cells can use to protect themselves from an immune attack and to elucidate the respective protective mechanism. This has already enabled us to describe many of the recently discovered immune-resistance mechanisms in various tumors.

e.g. Witzens-Harig et al. 2013, Blood;121(22):4493-503; Khandelwal et al., EMBO Mol Med. 2015 Feb 17;7(4):450-63; Volpin et al., Cancer Immunol Res 2020 Sep;8(9):1163-1179; Sorrentino et al., Journal for ImmunoTherapy of Cancer 2022; 10(5):e004258; Menevse et al., Acta Neuropathol Commun. 2023; 11(1):75

Activation of tumor cells by tumor specific T cells illustrated by calcium signals (white flares) within tumor cells upon attack by T cell.

02 | Regulation of anti-tumor immunity in situ

Here, we investigate the function of immune cells in human tumors—and how they can be altered—to characterize the determinants of successful and unsuccessful tumor immune control.

To this end, the division analyzes tumor-specific T cell responses in blood, bone marrow and tumor tissue, using single cell deep-sequencing methods among others. We use new toponomics approaches such as live cell imaging methods and single cell microdissections from tissue sections, as well as next generation sequencing and high performance computing to clarify functional interactions and cellular differentiation pathways in a temporal-spatial context. This is done in terms of molecular mechanics and enables us to identify factors that are important for successful tumor control by the immune system.

e.g. Xydia et al., Nature Communication 2021, 12, 1119; Ge et al., Cancer Immunol Res. 2019 Dec;7(12):1998-2012; Carretero et al., Nat Immunol. 2015 Jun;16(6):609-17; Reissfelder et al., J Clin Invest. 2015 Feb;125(2):739-51; Klug et al., Cancer Cell, 2013, dxdoi.org/10.1016/j.ccr2013.09.014; Bonertz et al., Journal of clinical investigation. 2009; 119: 3311-21., Nummer et al., Journal of the National Cancer Institute. 2007; 99: 1188-99

Tumor specific T cells convert in the tumor into either tumor promoting T cells or tumor killing T cells; Xydia et al., Nature Communication 2021, 12, 1119

03 | Breaking immune resistance

In this field, the team are developing therapeutic approaches to break down the immune resistance of tumors. Using our research program findings, we genetically reprogram immune cells so that they can specifically overcome tumor immune resistance. We also develop therapeutic procedures and drugs to support immune cells in their task to reject tumors.

e.g. Klug et al., Cancer Cell, 2013, dxdoi.org/10.1016/j.ccr2013.09.014, Sorrentino et al., Journal for ImmunoTherapy of Cancer 2022; 10(5):e004258; Pinkert et al. 2022, Oncoimmunology;11(1):2008110; Ge et al., Cancer immunology, immunotherapy : CII. 2012; 61: 353-62

One major focus of our investigations is the development of drugs that inhibit important immune-resistance mechanisms within tumor cells. The Division has recently identified a mechanism—based on the SIK3 kinase—that transforms cytotoxic signals from killer T cells into a tumor-activating signal that drives treatment resistance. A collaboration with the Biotec company iOmx AG has resulted in the development of a first-in-class inhibitor against SIK3 which entered clinical testing in 2023. e.g. Sorrentino et al., Journal for ImmunoTherapy of Cancer 2022; 10(5):e004258; Clinical Trials.gov Identifier: NCT05826600

Visit the complete list of our Research Division’s publications on Google Scholar:

https://scholar.google.com/citations?hl=en&hl=en&user=A_CVdsEAAAAJ

Here is a selection of the most important publications from the last few years:

Xydia M, Rahbari R, Ruggiero E, Macaulay I, Tarabichi M, Lohmayer R, Wilkening S, Michels T, Brown D, Vanuytven S, Mastitskaya S, Laidlaw S, Grabe N, Pritsch M, Fronza R, Hexel K, Schmitt S, Müller-Steinhardt M, Halama N, Domschke C, Schmidt M, von Kalle C, Schütz F, Voet T, Beckhove P. Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients. Nat Commun. 2021 Feb 18;12(1):1119. doi: 10.1038/s41467-021-21297-y. PMID: 33602930

Khandelwal N, Breinig M, Speck T, Michels T, Kreutzer C, Sorrentino A, Sharma AK, Umansky L, Conrad H, Poschke I, Offringa R, König R, Bernhard H, Machlenkin A, Boutros M, Beckhove P. A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes. EMBO Mol Med. 2015 Apr;7(4):450-63. doi: 10.15252/emmm.201404414. PMID: 25691366

Reissfelder C, Stamova S, Gossmann C, Braun M, Bonertz A, Walliczek U, Grimm M, Rahbari NN, Koch M, Saadati M, Benner A, Büchler MW, Jäger D, Halama N, Khazaie K, Weitz J, Beckhove P. Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis. J Clin Invest. 2015 Feb;125(2):739-51. doi: 10.1172/JCI74894. Epub 2014 Dec 22. PMID: 25562322

Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schäkel K, Garbi N, Jäger D, Weitz J, Schmitz-Winnenthal H, Hämmerling GJ, Beckhove P. Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013 Nov 11;24(5):589-602. doi: 10.1016/j.ccr.2013.09.014. Epub 2013 Oct 24. PMID: 24209604

Witzens-Harig M, Hose D, Jünger S, Pfirschke C, Khandelwal N, Umansky L, Seckinger A, Conrad H, Brackertz B, Rème T, Gueckel B, Meißner T, Hundemer M, Ho AD, Rossi JF, Neben K, Bernhard H, Goldschmidt H, Klein B, Beckhove P. Tumor cells in multiple myeloma patients inhibit myeloma-reactive T cells through carcinoembryonic antigen-related cell adhesion molecule-6. Blood. 2013 May 30;121(22):4493-503. doi: 10.1182/blood-2012-05-429415. Epub 2013 Apr 19. PMID: 23603913

Beckhove P, Warta R, Lemke B, Stoycheva D, Momburg F, Schnölzer M, Warnken U, Schmitz-Winnenthal H, Ahmadi R, Dyckhoff G, Bucur M, Jünger S, Schueler T, Lennerz V, Woelfel T, Unterberg A, Herold-Mende C. Rapid T cell-based identification of human tumor tissue antigens by automated two-dimensional protein fractionation. J Clin Invest. 2010 Jun;120(6):2230-42. doi: 10.1172/JCI37646. Epub 2010 May 10. PMID: 20458140

Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, Juenger S, Vlodavsky I, Khazaie K, Jaeger D, Reissfelder C, Antolovic D, Aigner M, Koch M, Beckhove P. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest. 2009 Nov;119(11):3311-21. doi: 10.1172/JCI39608. Epub 2009 Oct 5. PMID: 19809157

Nummer D, Suri-Payer E, Schmitz-Winnenthal H, Bonertz A, Galindo L, Antolovich D, Koch M, Büchler M, Weitz J, Schirrmacher V, Beckhove P. Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. J Natl Cancer Inst. 2007 Aug 1;99(15):1188-99. doi: 10.1093/jnci/djm064. Epub 2007 Jul 24. PMID: 17652277

Choi C, Witzens M, Bucur M, Feuerer M, Sommerfeldt N, Trojan A, Ho A, Schirrmacher V, Goldschmidt H, Beckhove P. Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma. Blood. 2005 Mar 1;105(5):2132-4. doi: 10.1182/blood-2004-01-0366. Epub 2004 Nov 23. PMID: 15561890

Beckhove P, Feuerer M, Dolenc M, Schuetz F, Choi C, Sommerfeldt N, Schwendemann J, Ehlert K, Altevogt P, Bastert G, Schirrmacher V, Umansky V. Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors. J Clin Invest. 2004 Jul;114(1):67-76. doi: 10.1172/JCI20278. PMID: 15232613

Feuerer M*, Beckhove P*, Garbi N*, Mahnke Y, Limmer A, Hommel M, Hämmerling GJ, Kyewski B, Hamann A, Umansky V, Schirrmacher V. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med. 2003 Sep;9(9):1151-7. doi: 10.1038/nm914. Epub 2003 Aug 10. PMID: 12910264 *; equal contributions

Feuerer M*, Beckhove P*, Bai L, Solomayer EF, Bastert G, Diel IJ, Pedain C, Oberniedermayr M, Schirrmacher V, Umansky V. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med. 2001 Apr;7(4):452-8. doi: 10.1038/86523. PMID: 11283672 *; equal contributions

The team are dedicated to developing innovative cell-therapy approaches for the treatment of patients with advanced cancer. Late-phase development projects include:

Antigen receptor transduced T cells with genetically engineered therapeutic payload

Immune checkpoint blockade by CEACAM6 inhibition is based on our identification of CEACAM6 as an important novel immune checkpoint molecule in many cancers. Together with the German Cancer Research Center we exploit a proprietary blocking antibody against this molecule which improves anti-cancer activity of tumor specific T cells. We have generated Antigen receptor transduced tumor specific T cells that produce and secrete this blocking antibody once they encounter a tumor cell so that their anti-tumor activity is improved. This concept is in preclinical development at the LIT.

Witzens-Harig et al. 2013, Blood;121(22):4493-503., Pinkert et al. 2022, Oncoimmunology;11(1):2008110

Inhibiting immune-resistance mechanisms

Our division has identified a novel immune resistance mechanism that is active in many cancers. It is based on the salt inducible kinase 3 which can transform a cytotoxic attack of a T cell into an activating, protumorigenic signal. Based on this finding, the spin off company iOmx —co-founded in 2016 by the division’s head Professor Beckhove— has developed a SIK3 inhibitor which has recently entered clinical testing.

Sorrentino et al., Journal for ImmunoTherapy of Cancer 2022; 10(5):e004258; Clinical Trials.gov Identifier: NCT05826600

Mode of action of CEACAM6 mediated T cell inhibition

Upon recognition of a tumor antigen on the MHC complex of a tumor cell by the T cell receptor (TCR) CEACAM6 recruits the inhibitory receptor CEACAM1 into the T cell receptor (TCR) synapse. CEACAM1 carries inhibitory motifs that activate the phsphatase SHP1 which inhbits the central TCR signalling molecule ZAP70 leading to abrogation of the TCR signal to the T cell. Witzens-Harig et al. 2013, Blood;121(22):4493-503

Human brest cancer cells (turquoise) express the immune checkpoint molecule CEACAM6 (purple)

T cells genetically engineered to exress an artificial receptor for tumor cell recognition (yellow) and blocking antibodies against CEACAM6 attack human breast cancer cells (turquoise)

The division participates in several national and international research consortia. These include:

SATURN3

This national research consortium to address ‘Spatial and Temporal Resolution of Intratumoral Heterogeneity in Three Hard-to-Treat Cancers’ is funded by the Federal Ministry of Education and Research (BmBF).

Clinical Research Consortium FOR 2858, SP A03

This consortium addresses ‘The Role of TSPO in T-Cell Immune Control Of Glioblastoma’ and is funded by the German Research Association (DFG, 2019-2025).

International consortium PAVE

‘A Nanovaccine Approach for the treatment of Pancreatic Cancer’ is an Integrated Training Network (ITN) funded by the European Union to develop peptide-based nanovaccines for pancreatic cancer (2020-2023).

T-Lock Consortium

This consortium unravels immune regulatory pathways in malignant melanoma, NSCLC and colorectal cancer (German Cancer Aid: 2019-2023)

Many thanks to the funding agencies who support our work:

Federal Ministry for Education and Research (BMBF) – SATURN3
‘Spatial and Temporal Resolution of Intratumoral Heterogeneity in Three Hard-To-Treat Cancers’

Website BMBF

German Research Association (DFG)
Clinical Research Consortium FOR 2858: ‘The role of TSPO in T-Cell Immune Control of Glioblastoma’

Website DFG

German Cancer Aid
T-Lock Consortium to unravel immune regulatory pathways in malignant melanoma, NSCLC and colorectal cancer

Website DKH

European Union EU-ITN – PAVE
‘A Nanovaccine Approach for the Treatment of Pancreatic Cancer’

Prof. Philipp Beckhove

Scientific Director
Head of Research Division | Interventional Immunology

Tel: +49 941 944–38101
Email: philipp.beckhove@lit.eu

Sabine Termer

Assistant to the Scientific Director
Team Assistant

Tel: +49 941 944–38102
Email: sabine.termer@ukr.de

Research team

Prof. Philipp Beckhove

Scientific Director LIT & Head of Research Division | Interventional Immunology

Dr. Ayse Nur Menevse

Postdoctoral Scientist

Dr. Slava Stamova

Postdoctoral Scientist

Dr. Maria Xydia

Postdoctoral Scientist

Abir Hussein

PhD Student

Alexander Wurzel

PhD Student

Meghma Mukherjee

PhD Student

Beril Kadioglu

Research Technician

Birgitta Ott-Rötzer

Research Technician

Leonard Bellersheim

MD Student

Alexander Glander

MD Student

Lab Life

There is life outside the laboratory: The Leibniz Institute places great value on our scientists developing the team spirit both in and out of work. Here are the photos to prove it!