γδ T-cell Receptors Derived from Breast Cancer–Infiltrating T Lymphocytes Mediate Antitumor Reactivity

γδ T cells in human solid tumors remain poorly defined. Here, we describe molecular and functional analyses of T-cell receptors (TCRs) from tumor-infiltrating γδ T lymphocytes (γδ TILs) that were in direct contact with tumor cells in breast cancer lesions from archival material. We observed that the majority of γδ TILs harbored a proinflammatory phenotype and only a minority associated with the expression of IL17. We characterized TCRγ or TCRδ chains of γδ TILs and observed a higher proportion of Vδ2+ T cells compared to other tumor types. By reconstructing matched Vδ2- TCRγ and TCRδ pairs derived from single-cell sequencing, our data suggest that γδ TILs could be active against breast cancer and other tumor types. The reactivity pattern against tumor cells depended on both the TCRγ and TCRδ chains and was independent of additional co-stimulation through other innate immune receptors. We conclude that γδ TILs can mediate tumor reactivity through their individual γδ TCR pairs and that engineered T cells expressing TCRγ and δ chains derived from γδ TILs display potent antitumor reactivity against different cancer cell types and, thus, may be a valuable tool for engineering immune cells for adoptive cell therapies.Fil: Janssen, Anke. University of Utrecht; Países BajosFil: Villacorta Hidalgo, Jose. Albert Ludwigs University of Freiburg; AlemaniaFil: Beringer, Dennis X. University of Utrecht; Países BajosFil: Van Dooremalen, Sanne. University of Utrecht; Países BajosFil: Febilla, Fernando. Utrecht University, Netherlands; ArgentinaFil: Van Diest, Eline. Utrecht University, Netherlands; ArgentinaFil: Terrizzi, Antonela Romina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Fisiología; ArgentinaFil: Bronser, Peter. Albert Ludwigs University of Freiburg; AlemaniaFil: Kock, Sylvia. Albert Ludwigs University of Freiburg; AlemaniaFil: Schmitt-Gräff, Annette. Albert Ludwigs University of Freiburg; AlemaniaFil: Werner, Martin. Albert Ludwigs University of Freiburg; AlemaniaFil: Fisch, Paul. Albert Ludwigs University of Freiburg; AlemaniaFil: Heise, Kerstin. University of Duisburg-Essen; AlemaniaFil: Follo, Marie. Albert Ludwigs University of Freiburg; AlemaniaFil: Straetemans, Trudy. University of Utrecht; Países BajosFil: Sebestyen, Zsolt. University of Utrecht; Países BajosFil: Chudakov, Dmitry M. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry; RusiaFil: Kasatskaya, Sofya A.. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry; RusiaFil: Kuball, Jurgen. University of Utrecht; Países BajosFil: Frenkel, Felix E.. No especifíca;Fil: Ravens, Sarina. Hannover Medical School; AlemaniaFil: Spierings, Eric. University of Utrecht; Países BajosFil: Prinz, Immo. Hannover Medical School; AlemaniaFil: Malkovsky, Miroslav. UW School of Medicine and Public Health; Estados UnidosFil: Fisch, Paul. Albert Ludwigs University of Freiburg; AlemaniaFil: Küppers, Ralf. University of Duisburg-Essen; Alemani