Immunology of MSI cancers

MSI tumors share an exceptional load of somatic mutations, which are the consequence of DNA mismatch repair deficiency. This high mutation load is accompanied by large numbers of MSI-specific neoantigens that can be recognized by the immune system. This pronounced immune responsiveness manifests in dense immune cell infiltrations typically observed in MSI cancers.

Our group has pioneered research on the immune biology of MSI cancers for many years. We were the first to show that patients affected by MSI cancer, but also tumor-free Lynch syndrome mutation carriers, show significant immune responses directed against MSI-specific neoantigens. These immune responses are particularly mediated by T cells, the most powerful cells in anti-tumoral immune responses of the adaptive immune system. Our current research activities are focused on the tumor-immune cell interplay and immune evasion mechanisms that enable MSI tumor cells to survive in a hostile immune environment. Understanding these mechanisms can lead to the development of improved therapeutic and tumor-preventive strategies.

Current projects


Publications / Output

Busch E, Ahadova A, Kosmalla K, Bohaumilitzky L, Pfuderer PL, Ballhausen A, Witt J, Wittemann JN, Bläker H, Holinski-Feder E, Jäger D, von Knebel Doeberitz M, Haag GM, Kloor M. Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers. Front Oncol. 2021 Jun 8;11:669774. eCollection 2021. PMID: 34168989

Ballhausen A, Przybilla MJ, Jendrusch M, Haupt S, Pfaffendorf E, Seidler F, Witt J, Hernandez Sanchez A, Urban K, Draxlbauer M, Krausert S, Ahadova A, Kalteis MS, Pfuderer PL, Heid D, Stichel D, Gebert J, Bonsack M, Schott S, Bläker H, Seppälä T, Mecklin JP, Ten Broeke S, Nielsen M, Heuveline V, Krzykalla J, Benner A, Riemer AB, von Knebel Doeberitz M, Kloor M. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nat Commun. 2020 Sep 21;11(1):4740. PMID: 32958755
Kloor M, Reuschenbach M, Pauligk C, Karbach J, Rafiyan MR, Al-Batran SE, Tariverdian M, Jäger E, von Knebel Doeberitz M. A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial. Clin Cancer Res. 2020 Sep 1;26(17):4503-4510. Epub 2020 Jun 15. PMID: 32540851
Bohaumilitzky L, von Knebel Doeberitz M, Kloor M, Ahadova A. Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review. J Clin Med. 2020 Jun 4;9(6):1741. PMID: 32512823
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 Aug;121(5):395-404. Epub 2019 Jul 30. PMID: 31358939

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.

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.

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.

Surmann EM, Voigt AY, Michel S, Bauer K, Reuschenbach M, Ferrone S, von Knebel Doeberitz M, Kloor M. Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer.Cancer Immunol Immunother. 2015 Mar;64(3):357-66. PMID: 25445815

Reuschenbach M, Dörre J, Waterboer T, Kopitz J, Schneider M, Hoogerbrugge N, Jäger E, Kloor M, von Knebel Doeberitz M. A multiplex method for the detection of serum antibodies against in silico-predicted tumor antigens.Cancer Immunol Immunother. 2014 Dec;63(12):1251-9. PMID: 25143232

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

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

Bauer K, Michel S, Reuschenbach M, Nelius N, von Knebel Doeberitz M, Kloor M. Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer.Fam Cancer. 2011 Sep;10(3):557-65. doi: 10.1007/s10689-011-9449-7. PMID: 21598004

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. doi: 10.1002/ijc.25283. 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

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. 2008 Apr;134(4):988-97. PMID: 18395080

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

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

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