Targeting exhausted cytotoxic T cells through CTLA-4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts.

Autor: Tavernari L; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Rontauroli S; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Norfo R; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Mirabile M; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Maccaferri M; Department Oncology and Hematology, Hematology Unit, Modena University Hospital, Modena, Italy., Mora B; Ospedale Maggiore Policlinico, Milan, Italy., Genovese E; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Parenti S; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Carretta C; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Bianchi E; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Bertesi M; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Pedrazzi F; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Tenedini E; Department of Laboratory Medicine, Diagnostic Hematology and Clinical Genomics Unit, Modena University Hospital, Modena, Italy., Martinelli S; Department of Laboratory Medicine, Diagnostic Hematology and Clinical Genomics Unit, Modena University Hospital, Modena, Italy., Bochicchio MT; Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy., Guglielmelli P; CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy.; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy., Potenza L; Department Oncology and Hematology, Hematology Unit, Modena University Hospital, Modena, Italy.; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy., Lucchesi A; Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy., Passamonti F; Ospedale Maggiore Policlinico, Milan, Italy.; University of Milan, Milan, Italy., Tagliafico E; Department of Laboratory Medicine, Diagnostic Hematology and Clinical Genomics Unit, Modena University Hospital, Modena, Italy.; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy., Luppi M; Department Oncology and Hematology, Hematology Unit, Modena University Hospital, Modena, Italy.; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy., Vannucchi AM; CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy.; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy., Manfredini R; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Jazyk: angličtina
Zdroj: American journal of hematology [Am J Hematol] 2024 Jul 02. Date of Electronic Publication: 2024 Jul 02.
DOI: 10.1002/ajh.27428
Abstrakt: Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.
(© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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