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

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

  • Am J Hematol. 2024 Jul 2. doi: 10.1002/ajh.27428.
Lara Tavernari 1 2,  Sebastiano Rontauroli 1 2,  Ruggiero Norfo 1 2,  Margherita Mirabile 1 2,  Monica Maccaferri 3,  Barbara Mora 4,  Elena Genovese 1 2,  Sandra Parenti 1 2,  Chiara Carretta 1 2,  Elisa Bianchi 1 5,  Matteo Bertesi 1 5,  Francesca Pedrazzi 1 5,  Elena Tenedini 6,  Silvia Martinelli 6,  Maria Teresa Bochicchio 7,  Paola Guglielmelli 8 9,  Leonardo Potenza 3 10,  Alessandro Lucchesi 11,  Francesco Passamonti 4 12,  Enrico Tagliafico 6 10 13,  Mario Luppi 3 10,  Alessandro Maria Vannucchi 8 9,  Rossella Manfredini 1 2,  MYNERVA (Myeloid NEoplasms Research Venture AIRC) investigators
Affiliations

Affiliations

  • 1 Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.
  • 2 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 3 Department Oncology and Hematology, Hematology Unit, Modena University Hospital, Modena, Italy.
  • 4 Ospedale Maggiore Policlinico, Milan, Italy.
  • 5 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 6 Department of Laboratory Medicine, Diagnostic Hematology and Clinical Genomics Unit, Modena University Hospital, Modena, Italy.
  • 7 Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
  • 8 CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy.
  • 9 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • 10 Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.
  • 11 Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
  • 12 University of Milan, Milan, Italy.
  • 13 Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.
PMID: 38953347 DOI: 10.1002/ajh.27428
Abstract

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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P9901
    99.88%, CTLA-4 Inhibitor