Purcarea and Jarosch et al. showed that partial protection from a neoantigen+ tumor was provided by transfer of as few as 128 neoantigen-specific T cells into irradiated host mice. PD-1, TIM-3, and LAG-3 had concerted expression on transferred T cells, which was highest on exhausted TILs. TCR avidity of transferred cells correlated with tumor protective peripheral blood T cells expressing PD-1 levels lower than in TILs, reflecting recent activation, but not with abundance or phenotype of neoantigen-specific TILs. In two patients with melanoma, neoantigen-specific TCRs were enriched among T cells expressing RNA and protein signatures of recent T cell activation.
Contributed by Paula Hochman
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.
Author Info: (1) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (2) Institute for Medical Microbiology, Immunology, and Hygi
Author Info: (1) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (2) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (3) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (4) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (5) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (6) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (7) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (8) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (9) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (10) BioTherapeutics Unit, Netherlands Cancer Institute, Amsterdam, Netherlands. (11) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (12) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands. (13) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. German Center for Infection Research (DZIF), Munich, Germany. Focus Group "Clinical Cell Processing and Purification", Institute for Advanced Study, TUM, Munich, Germany. (14) Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie, und Hygiene, Universittsklinikum Erlangen, Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany.
