Tracking antigen-specific T cell response to cancer immunotherapy

Shagina, I. A.; Nakonechanaya, T. O.; Izosimova, A. V.; Yuzhakova, D. V.; Skatova, V. D.; Lupyr, K. R.; Izraelson, M.; Davydov, A. N.; Shugay, M.; Britanova, O. V.; Chudakov, D. M.; Sharonov, G. V.

doi:10.1101/2024.11.29.626027

bioRxiv · 10.1101/2024.11.29.626027

Tracking antigen-specific T cell response to cancer immunotherapy

Shagina, I. A.·Nakonechanaya, T. O.·Izosimova, A. V.·Yuzhakova, D. V.·Skatova, V. D.·Lupyr, K. R.·Izraelson, M.·Davydov, A. N.·Shugay, M.·Britanova, O. V.·Chudakov, D. M.·Sharonov, G. V.

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Abstract

In each human or model animal, T cell receptor (TCR) of each effector/memory T cell clone recognizes from one to several cognate peptide-MHC complexes (pMHC). Limited knowledge on TCR repertoire specificities restricts our capacity to rationally interpret this information, both diagnostically and in preclinical research. Here we 1) develop cost-efficient wet lab and computational pipeline to identify mouse TCRs specific to particular peptides, 2) produce dataset of helper T cells (Th) TCR beta CDR3s specific to B16 melanoma neoantigens in the I-Ab pMHCII context, available in VDJdb, and 3) apply this dataset to track tumor-specific T cell response to the CTLA4 blocking immunotherapy on orthotopic B16 melanoma model. We show that tumor promotes clonally independent Tregs carrying tumor-specific TCRs characteristic for Th cells. We further show that CTLA4 blockade promotes Th clonal expansion and induces general, non-tumor-specific Th-to-Treg plasticity. Altogether, we provide a universal pipeline for the investigation of mouse T cell responses at the antigen-specific level, facilitating development and validation of immunotherapeutic and vaccination approaches.

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Shagina, I. A., Nakonechanaya, T. O., Izosimova, A. V., Yuzhakova, D. V., Skatova, V. D., Lupyr, K. R., Izraelson, M., Davydov, A. N., Shugay, M., Britanova, O. V., Chudakov, D. M., Sharonov, G. V.. 2024-12-03. Tracking antigen-specific T cell response to cancer immunotherapy. https://doi.org/10.1101/2024.11.29.626027

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