The clinical impact of microsatellite instability in colorectal cancer
Final Report Abstract
Topic of the subproject was the analysis of the clinical implications of MSI in colorectal cancer, with a main focus on the direct consequences of the immune biology of MSI cancers on tumor development, metastasis formation, and the clinical course of the disease. MSI cancers develop as a consequence of DNA mismatch repair deficiency and can occur either sporadically or in the context of Lynch syndrome, the most common inherited cancer syndrome with half a million affected individuals in Germany. In the first part of the project we have provided molecular characterization of all colorectal cancers included in the KFO227 study. In total, 127 (10.7%) out of 1182 tumors showed the MSI phenotype. MSI typing was complemented by KRAS and BRAF mutation analysis. MSI colorectal cancers are characterized by particularly strong immune responses of the host, because they accumulate numerous insertion/deletion mutations. In the second project part, we have evaluated immune evasion mechanisms in MSI cancers and established models to evaluate the consequences of immune evasion, namely B2M mutation-induced loss of HLA class I antigen expression, on the clinical behavior of the tumors. In the third project part, we have provided a detailed molecular characterization of MSI cancers and developed new analytical tools that led to the clarification of cancer pathogenesis pathways in Lynch syndrome. Major findings of the research projects were (1) the detailed and comprehensive characterization of the immune evasion mechanisms occurring in MSI colorectal cancer, (2) the establishment of B2M mutations as a true consequence of immune selection, (3) the first analysis of the consequences of B2M mutations on NK cell killing and metastasis formation, (4) the generation of new model systems to examine the consequences of immune evasion on the clinical course of cancer, (5) the clarification of the pathways leading to MSI colorectal cancer development in Lynch syndrome, providing a new explanation for the occurrence of interval cancers and explaining the clinical heterogeneity of MSI cancers, and (6) establishing a new tool for the comprehensive quantitative assessment of coding microsatellite mutations and frameshift peptide neoantigens in MSI cancers. Taken together, the results of our project underline that the heterogeneity of MSI colorectal cancers is rooted in differences of the host’s immune system, providing evidence that patients with high activity of local T cells in the colon mucosa are less likely developing tumors that have high metastatic potential. Thus, the results of the project strongly support the concept of integrating novel primary prevention measures that strengthen the host’s immune response against shared neoantigens of MSI cancer into the management of Lynch syndrome mutation carriers. This is of particular importance in Lynch syndrome, because a significant part of MSI colorectal cancers lack polypous pre-cancerous stages and therefore may be missed by colonoscopy. Together with the identification of highly immunogenic, recurrent neoantigens in MSI cancer, which directly result from driver mutation events, during the first funding period of the project, our data pave the way towards the development of a first cancer-preventive vaccine against a non-viral cancer in the model of MSI tumors and Lynch syndrome. The success of our first clinical trial that evaluated this approach underlines the feasibility of the approach. Demonstrating tumor prevention by a vaccine would have major impact on cancer prevention in general, as it would show that tumor prevention by specific modulation of the host’s immune system is feasible.
Publications
- Clinical significance of microsatellite instability in colorectal cancer. Langenbecks Arch Surg 399(1), 23-31 (2014)
Kloor M, Staffa L, Ahadova A, von Knebel Doeberitz M
(See online at https://doi.org/10.1007/s00423-013-1112-3) - Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndromeassociated colorectal cancer. Oncoimmunology 5(2), e1075692 (2015)
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
(See online at https://doi.org/10.1080/2162402X.2015.1075692) - Mismatch repair-deficient crypt foci in Lynch syndrome- -molecular alterations and association with clinical parameters. PLoS One 10(3), e0121980 (2015)
Staffa L, Echterdiek F, Nelius N, Benner A, Werft W, Lahrmann B, Grabe N, Schneider M, Tariverdian M, von Knebel Doeberitz M, Bläker H, Kloor M
(See online at https://doi.org/10.1371/journal.pone.0121980) - CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer 15(4), 579- 586 (2016)
Ahadova A, von Knebel Doeberitz M, Bläker H, Kloor M
(See online at https://doi.org/10.1007/s10689-016-9899-z) - The Immune Biology of Microsatellite-Unstable Cancer.Trends Cancer 2(3), 121-133 (2016)
Kloor M, von Knebel Doeberitz M
(See online at https://doi.org/10.1016/j.trecan.2016.02.004) - High numbers of PDCD1 (PD-1)-positive T cells and B2M mutations in microsatellite-unstable colorectal cancer. Oncoimmunology 7(2):e1390640 (2017)
Janikovits J, Müller M, Krzykalla J, Körner S, Echterdiek F, Lahrmann B, Grabe N, Schneider M, Benner A, von Knebel Doeberitz M, Kloor M
(See online at https://doi.org/10.1080/2162402X.2017.1390640) - Complex pattern of immune evasion in MSI colorectal cancer. Oncoimmunology Mar 26;7(7):e1445453 (2018)
Ozcan M, Janikovits J, von Knebel Doeberitz M, Kloor M
(See online at https://doi.org/10.1080/2162402X.2018.1445453) - Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer 143(1):139-150 (2018)
Ahadova A, Gallon R, Gebert J, Ballhausen A, Endris V, Kirchner M, Stenzinger A, Burn J, von Knebel Doeberitz M, Bläker H, Kloor M
(See online at https://doi.org/10.1002/ijc.31300)
