Analysis of Wilms' tumor protein 1 specific TCR repertoire in AML patients uncovers higher diversity in patients in remission than in relapsed

Gielis, S.; Flumens, D.; van der Heijden, S.; Versteven, M.; De Reu, H.; Bartholomeus, E.; Schippers, J.; Campillo-Davo, D.; Berneman, Z.; Anguille, S.; Smits, E.; Ogunjimi, B.; Lion, E.; Laukens, K.; Meysman, P.

doi:10.1101/2023.11.26.568717

bioRxiv · 10.1101/2023.11.26.568717

Analysis of Wilms' tumor protein 1 specific TCR repertoire in AML patients uncovers higher diversity in patients in remission than in relapsed

Gielis, S.·Flumens, D.·van der Heijden, S.·Versteven, M.·De Reu, H.·Bartholomeus, E.·Schippers, J.·Campillo-Davo, D.·Berneman, Z.·Anguille, S.·Smits, E.·Ogunjimi, B.·Lion, E.·Laukens, K.·Meysman, P.

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Abstract

The Wilms tumor protein 1 (WT1) is a well-known and prioritized tumor-associated antigen expressed in numerous solid and blood tumors. Its abundance and immunogenicity have led to the development of different WT1-specific immune therapies. The driving player in these therapies, the WT1-specific T-cell receptor (TCR) repertoire, has received much less attention. Importantly, T cells with high affinity against the WT1 self-antigen are normally eliminated after negative selection in the thymus and are thus rare in peripheral blood. Here, we developed computational models for the robust and fast identification of WT1-specific TCRs from TCR repertoire data. To this end, WT137-45 (WT1-37) and WT1126-134 (WT1-126)-specific T cells were isolated from WT1 peptide-stimulated blood of healthy individuals. The TCR repertoire from these WT1-specific T cells was sequenced and used to train a pattern recognition model for the identification of WT1-specific TCR patterns for the WT1-37 or WT1-126 epitopes. The resulting computational models were applied on an independent published dataset from acute myeloid leukemia (AML) patients, treated with hematopoietic stem cell transplantation, to track WT1-specific TCRs in silico. Several WT1-specific TCRs were found in AML patients. Subsequent clustering analysis of all repertoires indicated the presence of more diverse TCR patterns within the WT1-specific TCR repertoires of AML patients in complete remission in contrast to relapsing patients. We demonstrate the possibility of tracking WT1-37 and WT1-126-specific TCRs directly from TCR repertoire data using computational methods, eliminating the need for additional blood samples and experiments for the two studied WT1 epitopes.

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Gielis, S., Flumens, D., van der Heijden, S., Versteven, M., De Reu, H., Bartholomeus, E., Schippers, J., Campillo-Davo, D., Berneman, Z., Anguille, S., Smits, E., Ogunjimi, B., Lion, E., Laukens, K., Meysman, P.. 2023-11-26. Analysis of Wilms' tumor protein 1 specific TCR repertoire in AML patients uncovers higher diversity in patients in remission than in relapsed. https://doi.org/10.1101/2023.11.26.568717

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