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
  • 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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