MSI cancer

Microsatellite Instability (MSI) is one of the major phenotypes of genomic instability in human cancers. MSI is characterized by the accumulation of insertion/deletion mutations, which develop as a consequence of MMR deficiency. MSI cancers have a significantly elevated mutational load. Indels at defined coding microsatellites lead to the generation of frameshift peptide neoantigens. These neoantigens can be recognized by the host’s immune system and elicit a strong anti-tumor immune response.

Our group has pioneered research on the immune biology of MSI cancers and prepared the first-in-human vaccine against these cancers. This is particularly important, as it opens the possibility of tumor-preventive vaccines for Lynch syndrome patients who have an inherited predisposition to develop MSI cancer (for more information on MSI cancer pathogenesis click here).

Our main research directions

Our team

Preprints

Ballhausen APrzybilla MJJendrusch M, Haupt SPfaffendorf EDraxlbauer MSeidler FKrausert SAhadova AKalteis MSHeid DGebert JBonsack MSchott SBläker HSeppälä TMecklin JP, Ten Broeke SNielsen MHeuveline VKrzykalla JBenner ARiemer AB, von Knebel Doeberitz MKloor M. The shared neoantigen landscape of MSI cancers reflects immunoediting during tumor evolution. bioRxiv.  July 16, 2019. doi: https://doi.org/10.1101/691469

Recent publications

Engel C, Ahadova A, Seppälä T, Aretz S, Bigirwamungu-Bargeman M, Bläker H, Bucksch K, Büttner R, de Vos Tot Nederveen Cappel W, Endris V, Holinski-Feder E, Holzapfel S, Hüneburg R, Jacobs MAJM, Koornstra JJ, Langers AM, Lepistö A, Morak M, Möslein G, Peltomäki P, Pylvänäinen K, Rahner N, Renkonen-Sinisalo L, Schulmann K, Steinke-Lange V, Stenzinger A, Strassburg CP, van de Meeberg PC, van Kouwen M, van Leerdam M, Vangala DB, Vecht J, Verhulst ML, von Knebel Doeberitz M, Weitz J, Zachariae S, Loeffler M, Mecklin JP, Kloor M, Vasen HF; German HNPCC Consortium, the Dutch Lynch Syndrome Collaborative Group, and the Finnish Lynch Syndrome Registry. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology. 2020 Jan 8. pii: S0016-5085(20)30014-7. doi: 10.1053/j.gastro.2019.12.032. [Epub ahead of print] PMID: 31926173

Pfuderer PL, Ballhausen A, Seidler F, Stark HJ, Grabe N, Frayling IM, Ager A, von Knebel Doeberitz M, Kloor M, Ahadova A. High endothelial venules are associated with microsatellite instability, hereditary background and immune evasion in colorectal cancer. Br J Cancer. 2019 Jul 30  doi: 10.1038/s41416-019-0514-6. PMID: 31358939

Haag GM, Czink E, Ahadova A, Schmidt T, Sisic L, Blank S, Heger U, Apostolidis L, Berger AK, Springfeld C, Lasitschka F, Jäger D, von Knebel Doeberitz M, Kloor M. Prognostic significance of microsatellite-instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy. Int J Cancer. 2019 Apr 1;144(7):1697-1703. doi: 10.1002/ijc.32030. Epub 2019 Jan 4. PMID: 30499151

Ozcan M, Janikovits J, von Knebel Doeberitz M, Kloor M. Complex pattern of immune evasion in MSI colorectal cancer. Oncoimmunology. 2018 Mar 26;7(7):e1445453. PMID: 29900056

Ahadova A, Gallon R, Gebert J, Ballhausen A, Endris V, Kirchner M, Stenzinger A, Burn J, von Knebel Doeberitz M, Bläker H, Kloor M. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer. 2018 Jul 1. PMID: 29424427

Fricke F, Lee J, Michalak M, Warnken U, Hausser I, Suarez-Carmona M, Halama N, Schnölzer M, Kopitz J, Gebert J. TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells. Cell Commun Signal. 2017 Apr 4;15(1):14. PMID: 28376875

Janikovits J, Müller M, Krzykalla J, Körner S, Echterdiek F, Lahrmann B, Grabe N, Schneider M, Benner A, Doeberitz MVK, Kloor M. High numbers of PDCD1 (PD-1)-positive T cells and B2Mmutations in microsatellite-unstable colorectal cancer. Oncoimmunology. 2017 Nov 6;7(2):e1390640. PMID: 29308317

Ahadova A, von Knebel Doeberitz M, Bläker H, Kloor M. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer. 2016 Oct;15(4):579-86. PMID: 26960970

Kloor M, von Knebel Doeberitz M. The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer. 2016 Mar;2(3):121-133. Review. PMID: 28741532

Echterdiek F, Janikovits J, Staffa L, Müller M, Lahrmann B, Frühschütz M, Hartog B, Nelius N, Benner A, Tariverdian M, von Knebel Doeberitz M, Grabe N, Kloor M. Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer. Oncoimmunology. 2015 Nov 11;5(2):e1075692. PMID: 27057447.

Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014 Apr 26;383(9927):1490-1502. PMID: 24225001

von Knebel Doeberitz M, Kloor M. Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam Cancer. 2013 Jun;12(2):307-12. doi: 10.1007/s10689-013-9662-7. Review. PMID: 23760517

Capper D, Voigt A, Bozukova G, Ahadova A, Kickingereder P, von Deimling A, von Knebel Doeberitz M, Kloor M. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer. Int J Cancer. 2013 Oct 1;133(7):1624-30. PMID: 23553055

Kloor M, Huth C, Voigt AY, Benner A, Schirmacher P, von Knebel Doeberitz M, Bläker H. Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol. 2012 Jun;13(6):598-606. PMID: 22552011

Tikidzhieva A, Benner A, Michel S, Formentini A, Link KH, Dippold W, von Knebel Doeberitz M, Kornmann M, Kloor M. Microsatellite instability and Beta2-Microglobulin mutations as prognostic markers in colon cancer: results of the FOGT-4 trial. Br J Cancer. 2012 Mar 13;106(6):1239-45. PMID: 22353804

Kloor M, Voigt AY, Schackert HK, Schirmacher P, von Knebel Doeberitz M, Bläker H. Analysis of EPCAM protein expression in diagnostics of Lynch syndrome. J Clin Oncol. 2011 Jan 10;29(2):223-7. doi: 10.1200/JCO.2010.32.0820. Epub 2010 Nov 29. PMID: 21115857

Kloor M, Michel S, von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int J Cancer. 2010 Sep 1;127(5):1001-10. Review. PMID: 20198617

Michel S, Linnebacher M, Alcaniz J, Voss M, Wagner R, Dippold W, Becker C, von Knebel Doeberitz M, Ferrone S, Kloor M. Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes. Int J Cancer. 2010 Aug 15;127(4):889-98. PMID: 20013806

Reuschenbach M, Kloor M, Morak M, Wentzensen N, Germann A, Garbe Y, Tariverdian M, Findeisen P, Neumaier M, Holinski-Feder E, von Knebel Doeberitz M. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome. Fam Cancer. 2010 Jun;9(2):173-9. PMID: 19957108

Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol. 2009 Sep;10(9):840-1. PMID: 19717085

Roeckel N, Woerner SM, Kloor M, Yuan YP, Patsos G, Gromes R, KopitzJ, Gebert J. High frequency of LMAN1 abnormalities in colorectal tumors with microsatellite instability. Cancer Res. 2009 Jan 1;69(1):292-9. PMID:19118014

Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, Grabe N, von Knebel Doeberitz M, Kloor M. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008 Dec 2;99(11):1867-73. PMID: 18985040

Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel Doeberitz M. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 2008 Apr;134(4):988-97. PMID: 18395080

Korff S, Woerner SM, Yuan YP, Bork P, von Knebel Doeberitz M, Gebert J. Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability. BMC Cancer. 2008 Nov 10;8:329. PMID: 19000305

Kloor M, Michel S, Buckowitz B, Rüschoff J, Büttner R, Holinski-Feder E, Dippold W, Wagner R, Tariverdian M, Benner A, Schwitalle Y, Kuchenbuch B, von Knebel Doeberitz M. Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int J Cancer. 2007 Jul 15;121(2):454-8. PMID: 17373663

Woerner SM, Kloor M, von Knebel Doeberitz M, Gebert JF. Microsatellite instability in the development of DNA mismatch repair deficient tumors. Cancer Biomark. 2006;2(1-2):69-86. Review. PMID: 17192061

Kloor M, Becker C, Benner A, Woerner SM, Gebert J, Ferrone S, von Knebel Doeberitz M. Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res. 2005 Jul 15;65(14):6418-24. PMID: 16024646

Wüllenweber HP, Sutter C, Autschbach F, Willeke F, Kienle P, Benner A, Bähring J, Kadmon M, Herfarth C, von Knebel Doeberitz M, Gebert J. Evaluation of Bethesda guidelines in relation to microsatellite instability. Dis Colon Rectum. 2001 Sep;44(9):1281-9. PMID: 11584201

Haack K, Linnebacher M, Eisold S, Zöller M, von Knebel Doeberitz M, Gebert J. Induction of protective immunity against syngeneic rat cancer cells by expression of the cytosine deaminase suicide gene. Cancer Gene Ther. 2000 Oct;7(10):1357-64. PMID: 11059694

Gebert J, Sun M, Ridder R, Hinz U, Lehnert T, Möller P, Schackert HK, Herfarth C, von Knebel Doeberitz M. Molecular profiling of sporadic colorectal tumors by microsatellite analysis. Int J Oncol. 2000 Jan;16(1):169-79. PMID: 10601563

Recent grants

We are dedicated to connecting basic research and clinic. Therefore we are highly interested in unraveling biological mechanisms that may be used for development of therapeutic and preventive approaches. Our research on development of the first vaccine for MSI cancers was awarded with Felix Burda Award 2015 in the category “Medicine and Science”.

Our collaborators

Prof. John Burn, Institute of Genetic Medicine, Newcastle University, UK

Prof. Jukka-Pekka Mecklin, Jyväskylä University, Finland

Prof. Elke Jäger, Krankehaus Nordwest, Frankfurt, Germany

Prof. Salah-Eddin Albatran, Krankehaus Nordwest, Frankfurt, Germany

Prof. Hendrik Bläker, Charite Berlin, Germany

Prof. Annete Paschen, University Hospital Essen, Germany

Prof. Gabriela Möslein, Helios Klinik, Wuppertal, Germany

Prof. Alex Duval, Sorbonne University, Paris, France

Dr. Steven Lipkin, Weill Cornell University, New York, US

Dr. Robert Shoemaker, NCI, Washington, US

Dr. Asad Umar, NCI, Washington, US

Dr. Pål Møller, Oslo University, Norway

Dr. Toni Seppälä, Helsinki University, Finland

Dr. Ian Frayling, University of Cardiff, UK

Dr. Mirjam Tariverdian, University Hospital Heidelberg, Germany

Dr. Peer Bork, EMBL, Heidelberg. Germany

Activities in clinical and scientific organizations