biostudies-literatureCerapio JPInstitut Universitaire du Cancer de Toulouse-Oncopole under contract CIELFondation ARC pour la Recherche sur le CancerLabEx Toulouse CancerLaboratoire d’Excellence Toulouse Cancerthe Institut National de la Santé et de la Recherche MédicaleInstitut Carnot CALYMthe Université Toulouse III-Paul Sabatier, the Centre National de la Recherche ScientifiqueInstitut Carnot Lymphome under cointract CALYM1939518https://www.ebi.ac.uk/biostudies/studies/S-EPMC8555559biostudies-literatureUnknown10(1)γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor's blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.OncoimmunologyPhased differentiation of γδ T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers.PMC8555559RAC21009BAPGA1 RF20190208691ANR11-LABXFournie JJQuillet-Mary AYsebaert LAyyoub MBalanca CCFranchini DMDevaud CPerrier MDelord JPCerapio JPLopez FGravelle PPont FMartinez ATosolini MLaurent CFeliu VValle CfalsePhased differentiation of γδ T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers.γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor's blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.2021-01-01T00:00:00Z20212025-04-04T14:09:47.421Z2025-04-04T14:09:47.421ZS-EPMC85555593472194510.1080/2162402X.2021.1939518