We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity.
- Authors
Purcarea, Anna; Jarosch, Sebastian; Barton, Jack; Grassmann, Simon; Pachmayr, Ludwig; D'Ippolito, Elvira; Hammel, Monika; Hochholzer, Anna; Wagner, Karolin I.; van den Berg, Joost H.; Buchholz, Veit R.; Haanen, John B. A. G.; Busch, Dirk H.; Schober, Kilian
- Abstract
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. Activate and protect: T cells are key to anti-tumor immune responses and their ability to strongly engage antigen on tumors is crucial to their efficacy. Here, Purcarea and Jarosch et al. studied how T cell receptor (TCR) avidity of tumor-specific T cells affected their anti-tumor capabilities using mouse modeling and two melanoma patients. In mice, they found that high-avidity TCR T cells were better able to slow tumor growth, despite being present at similar levels and having a similar exhaustion phenotype as low-avidity TCR T cells in tumors. In the circulation of mice and patients, however, these tumor-protective, high-avidity TCR T cells had a recently activated phenotype compared with low-avidity TCR T cells. Thus, protective T cells in circulation are likely recently activated.
- Subjects
ANTIGEN receptors; T cells; T cell receptors; PROGRAMMED cell death 1 receptors; CELL populations
- Publication
Science Immunology, 2022, Vol 7, Issue 74, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abm2077