Purcarea A, Jarosch S, Barton J, Grassmann S, Pachmayr L, D'Ippolito E, Hammel M, Hochholzer A, Wagner KI, van den Berg JH, Buchholz VR, Haanen JB, Busch DH, Schober K (2022)
Publication Type: Journal article
Publication year: 2022
Book Volume: 7
Pages Range: eabm2077-
Journal Issue: 74
DOI: 10.1126/sciimmunol.abm2077
T cell receptor (TCR) avidity is assumed to be a major determinant of the spatiotemporal fate and protective capacity of tumor-specific T cells. However, monitoring polyclonal T cell responses with known TCR avidities in vivo over space and time remains challenging. Here, we investigated the fate and functionality of tumor neoantigen-specific T cells with TCRs of distinct avidities in a well-established, reductionist preclinical tumor model and human patients with melanoma. To this end, we used polyclonal T cell transfers with in-depth characterized TCRs together with flow cytometric phenotyping in mice inoculated with MC38 OVA tumors. Transfer of T cells from retrogenic mice harboring TCRs with high avidity resulted in best tumor protection. Unexpectedly, we found that both high- and low-avidity T cells are similarly abundant within the tumor and adopt concordant phenotypic signs of exhaustion. Outside the tumor, high-avidity TCR T cells were not generally overrepresented but, instead, selectively enriched in T cell populations with intermediate PD-1 protein expression. Single-cell sequencing of neoantigen-specific T cells from two patients with melanoma-combined with transgenic reexpression of identified TCRs by CRISPR-Cas9-mediated orthotopic TCR replacement-revealed high-functionality TCRs to be enriched in T cells with RNA signatures of recent activation. Furthermore, of 130 surface protein candidates, PD-1 surface expression was most consistently enriched in functional TCRs. Together, our findings show that tumor-reactive TCRs with high protective capacity circulating in peripheral blood are characterized by a signature of recent activation.
APA:
Purcarea, A., Jarosch, S., Barton, J., Grassmann, S., Pachmayr, L., D'Ippolito, E.,... Schober, K. (2022). Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity. Science immunology, 7(74), eabm2077-. https://doi.org/10.1126/sciimmunol.abm2077
MLA:
Purcarea, Anna, et al. "Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity." Science immunology 7.74 (2022): eabm2077-.
BibTeX: Download