| Autor: |
Anna Purcarea, Sebastian Jarosch, Jack Barton, Simon Grassmann, Ludwig Pachmayr, Elvira D’Ippolito, Monika Hammel, Anna Hochholzer, Karolin I. Wagner, Joost H. van den Berg, Veit R. Buchholz, John B. A. G. Haanen, Dirk H. Busch, Kilian Schober |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Science immunology. 7(74) |
| ISSN: |
2470-9468 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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