biostudies-literatureManfredi FAcademy of FinlandAssociazione Italiana per la Ricerca sul CancroItalian Ministry of Health and Alliance Against Cancer (Ricerca CorrenteItalian Ministry of Education, University and Researcheadg8014https://www.ebi.ac.uk/biostudies/studies/S-EPMC10691777biostudies-literatureUnknown9(48)To study and then harness the tumor-specific T cell dynamics after allogeneic hematopoietic stem cell transplant, we typed the frequency, phenotype, and function of lymphocytes directed against tumor-associated antigens (TAAs) in 39 consecutive transplanted patients, for 1 year after transplant. We showed that TAA-specific T cells circulated in 90% of patients but display a limited effector function associated to an exhaustion phenotype, particularly in the subgroup of patients deemed to relapse, where exhausted stem cell memory T cells accumulated. Accordingly, cancer-specific cytolytic functions were relevant only when the TAA-specific T cell receptors (TCRs) were transferred into healthy, genome-edited T cells. We then exploited trogocytosis and ligandome-on-chip technology to unveil the specificities of tumor-specific TCRs retrieved from the exhausted T cell pool. Overall, we showed that harnessing circulating TAA-specific and exhausted T cells allow to isolate TCRs against TAAs and previously not described acute myeloid leukemia antigens, potentially relevant for T cell-based cancer immunotherapy.Science advancesHarnessing T cell exhaustion and trogocytosis to isolate patient-derived tumor-specific TCR.PMC10691777RCR-2019-23669115PRIN 2017WC8499309608 AND 325222AIRC-IG 18458 AND AIRC 5 PER MILLE 22737Manfredi FFeola SBalestrieri CCianciotti BCAbbati DLehtio JCerullo VMagnani ZCiceri FVago LBonini CTassi ESikanen TMPotenza APunta MMarzuttini FCamisa BStasi LCasucci MNoviello MHaapala MJMastaglio SRuggiero EToffalori CBranca RMTiziano EBuonanno SLupo-Stanghellini MTfalseHarnessing T cell exhaustion and trogocytosis to isolate patient-derived tumor-specific TCR.To study and then harness the tumor-specific T cell dynamics after allogeneic hematopoietic stem cell transplant, we typed the frequency, phenotype, and function of lymphocytes directed against tumor-associated antigens (TAAs) in 39 consecutive transplanted patients, for 1 year after transplant. We showed that TAA-specific T cells circulated in 90% of patients but display a limited effector function associated to an exhaustion phenotype, particularly in the subgroup of patients deemed to relapse, where exhausted stem cell memory T cells accumulated. Accordingly, cancer-specific cytolytic functions were relevant only when the TAA-specific T cell receptors (TCRs) were transferred into healthy, genome-edited T cells. We then exploited trogocytosis and ligandome-on-chip technology to unveil the specificities of tumor-specific TCRs retrieved from the exhausted T cell pool. Overall, we showed that harnessing circulating TAA-specific and exhausted T cells allow to isolate TCRs against TAAs and previously not described acute myeloid leukemia antigens, potentially relevant for T cell-based cancer immunotherapy.2023-01-01T00:00:00Z2023 Dec2026-06-23T03:17:20.241Z2025-02-19T01:18:09.597ZS-EPMC106917773803936410.1126/sciadv.adg8014