N49: A Mouse Model For Proof Of Concept Of A Vaccine Against Lynch Syndrome-Associated Cancers

M. Kloor1, M. Ozcan2, A. Ahadova2, Y. Yuan3, P. Bork3, S. Sei4, R. Shoemaker4, Ö. Gelincik4, S. Lipkin4, J. Gebert2, M. von Knebel Doeberitz2

1 – Department of Applied Tumor Biology, University Hospital Heidelberg. 2 – University Hospital Heidelberg. 3 – European Molecular Biology Laboratory. 4 – National Cancer Institute (US)


Aim: Microsatellite-unstable (MSI) cancers occurring in Lynch syndrome elicit pronounced immune responses directed against frameshift peptide (FSP) neoantigens. Our group could demonstrate the existence of shared FSP neoantigens in MSI cancer and detected spontaneous FSP-specific immune responses in affected patients. To further develop the concept of a cancer-preventive vaccine in Lynch syndrome, we aimed to establish a preclinical mouse model.

Method: A systematic database search was performed to identify coding microsatellites (cMS) and potential neoantigens in Lynch syndrome mice (Msh2flox/floxVpC+/+). After mutation analysis of murine tumors, most promising FSP neoantigens were evaluated for immunogenicity by ELISpot after vaccination of C57BL/6 mice.

Results: Four FSP neoantigens derived from common cMS mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular and humoral immune responses. Based on the cMS mutation data, a vaccine with these four FSP neoantigens is predicted to cover about 75% of cancers in Lynch mice.

Conclusion: We have identified four immunogenic FSP neoantigens derived from commonly mutated cMS in murine Lynch syndrome colorectal cancers. This allows evaluating the concept of cancer-preventive neoantigen vaccines in mouse models of Lynch syndrome, including longitudinal monitoring of immune responses and combination with different adjuvants and chemoprevention approaches.