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

Author:

Tavernari Lara12ORCID,Rontauroli Sebastiano12ORCID,Norfo Ruggiero12,Mirabile Margherita12,Maccaferri Monica3,Mora Barbara4,Genovese Elena12,Parenti Sandra12,Carretta Chiara12ORCID,Bianchi Elisa15,Bertesi Matteo15,Pedrazzi Francesca15,Tenedini Elena6,Martinelli Silvia6,Bochicchio Maria Teresa7,Guglielmelli Paola89,Potenza Leonardo310,Lucchesi Alessandro11ORCID,Passamonti Francesco412,Tagliafico Enrico61013ORCID,Luppi Mario310,Vannucchi Alessandro Maria89ORCID,Manfredini Rossella12ORCID,

Affiliation:

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

Abstract

AbstractMyeloproliferative 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.

Funder

Ministero dell'Università e della Ricerca

Fondazione AIRC per la ricerca sul cancro ETS

Publisher

Wiley

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