期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 17, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI152585
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资金
- Bristol-Myers Squibb
- Nordic Cancer Union
- Academy of Finland
- Signe and Ane Gyllenberg Foundation
- Helsinki Institute of Life Science
- Finn- ish Cancer Institute
- Cancer Foundation Finland
- EUTOS project for CML 2018
- ERA-Net ERACoSysMed JTC-2 project prediCt,
- Relander Foundation
- Helsinki Institute for Life Science
- Biomedicum Helsinki Foundation
- Finnish Medical Foundation,
- K. Albin Johansson Foundation
- Kaute Foundation
- Emil Aaltonen Foundation
In patients with chronic myeloid leukemia, combination therapy with dasatinib and IFN-alpha can improve deep molecular remission and restore immune function.
In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-alpha is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-alpha in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR beta sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8(+) recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-alpha reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-alpha had costimulatory effects on TCR signaling. Our work supports the combination of IFN-alpha with TKI therapy, as IFN-alpha broadens the immune repertoire and restores immunological function.
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