Isolation of neoantigen-specific human T cell receptors from different human and murine repertoires

Grunert, C.; Willimsky, G.; Peuker, C.A.; Rhein, S.; Hansmann, L.; Blankenstein, T.; Blanc, E.; Beule, D.; Keller, U.; Pezzutto, A.; Busse, A.

Isolation of neoantigen-specific human T cell receptors from different human and murine repertoires

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Item Type:	Article
Title:	Isolation of neoantigen-specific human T cell receptors from different human and murine repertoires
Creators Name:	Grunert, C., Willimsky, G., Peuker, C.A., Rhein, S., Hansmann, L., Blankenstein, T., Blanc, E., Beule, D., Keller, U., Pezzutto, A. and Busse, A.
Abstract:	(1) Background: Mutation-specific T cell receptor (TCR)-based adoptive T cell therapy represents a truly tumor-specific immunotherapeutic strategy. However, isolating neoepitope-specific TCRs remains a challenge. (2) Methods: We investigated, side by side, different TCR repertoires-patients' peripheral lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs), PBLs of healthy donors, and a humanized mouse model-to isolate neoepitope-specific TCRs against eight neoepitope candidates from a colon cancer and an ovarian cancer patient. Neoepitope candidates were used to stimulate T cells from different repertoires in vitro to generate neoepitope-specific T cells and isolate the specific TCRs. (3) Results: We isolated six TCRs from healthy donors, directed against four neoepitope candidates and one TCR from the murine T cell repertoire. Endogenous processing of one neoepitope, for which we isolated one TCR from both human and mouse-derived repertoires, could be shown. No neoepitope-specific TCR could be generated from the patients' own repertoire. (4) Conclusion: Our data indicate that successful isolation of neoepitope-specific TCRs depends on various factors such as the heathy donor's TCR repertoire or the presence of a tumor microenvironment allowing neoepitope-specific immune responses of the host. We show the advantage and feasibility of using healthy donor repertoires and humanized mouse TCR repertoires to generate mutation-specific TCRs with different specificities, especially in a setting when the availability of patient material is limited.
Keywords:	Neoantigens, T Cell Receptor (TCR) Therapy, Tumor-Specific TCR, Antigen-Specific T Cell, T Cell Receptor Repertoire, Animals, Mice
Source:	Cancers
ISSN:	2072-6694
Publisher:	MDPI
Volume:	14
Number:	7
Page Range:	1842
Date:	6 April 2022
Official Publication:	https://doi.org/10.3390/cancers14071842
PubMed:	View item in PubMed

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