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 IFN gamma and TNF alpha. 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.

Targeting exhausted cytotoxic T cells through CTLA‐4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts / Tavernari, Lara; Rontauroli, Sebastiano; Norfo, Ruggiero; Mirabile, Margherita; Maccaferri, Monica; Mora, Barbara; Genovese, Elena; Parenti, Sandra; Carretta, Chiara; Bianchi, Elisa; Bertesi, Matteo; Pedrazzi, Francesca; Tenedini, Elena; Martinelli, Silvia; Bochicchio, Maria Teresa; Guglielmelli, Paola; Potenza, Leonardo; Lucchesi, Alessandro; Passamonti, Francesco; Tagliafico, Enrico; Luppi, Mario; Vannucchi, Alessandro Maria; Manfredini, Rossella; Null, Null. - In: AMERICAN JOURNAL OF HEMATOLOGY. - ISSN 0361-8609. - 99:10(2024), pp. 1939-1950. [10.1002/ajh.27428]

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

Tavernari, Lara;Rontauroli, Sebastiano;Norfo, Ruggiero;Mirabile, Margherita;Maccaferri, Monica;Genovese, Elena;Parenti, Sandra;Carretta, Chiara;Bianchi, Elisa;Bertesi, Matteo;Pedrazzi, Francesca;Tenedini, Elena;Potenza, Leonardo;Tagliafico, Enrico;Luppi, Mario;Vannucchi, Alessandro Maria;Manfredini, Rossella;
2024

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 IFN gamma and TNF alpha. 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
99
10
1939
1950
Targeting exhausted cytotoxic T cells through CTLA‐4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts / Tavernari, Lara; Rontauroli, Sebastiano; Norfo, Ruggiero; Mirabile, Margherita; Maccaferri, Monica; Mora, Barbara; Genovese, Elena; Parenti, Sandra; Carretta, Chiara; Bianchi, Elisa; Bertesi, Matteo; Pedrazzi, Francesca; Tenedini, Elena; Martinelli, Silvia; Bochicchio, Maria Teresa; Guglielmelli, Paola; Potenza, Leonardo; Lucchesi, Alessandro; Passamonti, Francesco; Tagliafico, Enrico; Luppi, Mario; Vannucchi, Alessandro Maria; Manfredini, Rossella; Null, Null. - In: AMERICAN JOURNAL OF HEMATOLOGY. - ISSN 0361-8609. - 99:10(2024), pp. 1939-1950. [10.1002/ajh.27428]
Tavernari, Lara; Rontauroli, Sebastiano; Norfo, Ruggiero; Mirabile, Margherita; Maccaferri, Monica; Mora, Barbara; Genovese, Elena; Parenti, Sandra; C...espandi
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