Dasatinib promotes the potential of proliferation and antitumor responses of human γδT cells in a long-term induction ex vivo environment

Wu, Kan; Wang, Y J; Hu, Ying; Fu, Haidong; Sheng, Lixia; Wang, B S; Fu, Shan; Huang, He

doi:10.1038/leu.2013.221

Cited by 12 publications

(17 citation statements)

References 15 publications

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“…P < 0.001 in all models analyzed by a two-way ANOVA test. (15), the results could suggest an important role for NK cells, as they are known to exhibit antitumor activity against B16 melanoma cells (32), and they can induce CD8 þ T-cell activation (33). Also, in our experiments, the number and degranulation function of NK cells was enhanced.…”

Section: Discussionsupporting

confidence: 55%

“…However, despite this rapid mobilization, the total number of blood lymphocytes decreased at later treatment days, while the proportion of CD8 þ T cells, monocytes, granulocytes, and NK cells increased. This could be due to celltype and dose-dependent effects of dasatinib as a recent ex vivo study by Wu and colleagues demonstrated that CD8 þ T cells and NK cells react differently to dasatinib exposure depending on incubation times and concentrations used (15). At lower doses, dasatinib increased the expansion of gd T cells, whereas higher doses inhibited them, but increased the number and function of NK cells.…”

Section: Discussionmentioning

confidence: 90%

“…A short exposure to dasatinib can actually activate NK cells (12,13). Similarly, in clinical use, immunostimulatory effects have been observed during the long-term use of dasatinib (14)(15)(16)(17). For example, in a subset of leukemia patients, dasatinib treatment causes a clonal expansion of large granular lymphocytes (LGL) in blood, including expansion of CD8 þ T cells and NK cells (17,18) and a decrease of regulatory T cells (Treg; refs.…”

Section: Introductionmentioning

confidence: 99%

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Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Hekim

Ilander

Yan

et al. 2017

Cancer Immunology Research

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Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8 þ T cells in PB, together with a higher amount of tumor-infiltrating CD8 þ T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4 þ and CD8 þ T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Hekim

Ilander

Yan

et al. 2017

Cancer Immunology Research

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“…Vγ9Vδ2 T cell is important immune cell in peripheral blood and are attractive candidate for the elimination of leukemia cells (20)(21)(22)(23). Consistent with an earlier study, we have previously shown that Vγ9Vδ2 T cells can effectively recognize and kill CML cells (23)(24)(25). Both HCQ and Vγ9Vδ2 T cells are promising in CML treatment, but the effects of HCQ on the elimination of CML cells by Vγ9Vδ2 T cells are unknown.…”

Section: Introductionsupporting

confidence: 85%

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Han

Zhao

Lin

et al. 2017

International Journal of Oncology

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Hydroxychloroquine (HCQ) is the only autophagy inhibitor in clinical use and it has shown great potential in treating chronic myeloid leukemia (CML). By inhibiting autophagy, HCQ enhances the anti-CML efficiency of chemotherapy. In the present study, we demonstrated that HCQ sensitized CML cells to Vγ9Vδ2 T cell-mediated lysis. HCQ inhibited autophagy in CML cells, but the sensitizing effects of HCQ were autophagy-independent. Since the sensitization was not mimicked by ATG7 knockdown and even occurred in the absence of ATG7. We revealed that in a time-dependent manner HCQ induced the expression of NKG2D ligand ULBP4 on the surface of CML cells. This marks the leukemia cell for recognition by Vγ9Vδ2 T cells. Blocking the interaction of NKG2D with its ligands deleted the sensitizing effects of HCQ. In addition, we showed that HCQ did not affect the synthesis or degradation of ULBP4, but induced the translocation of ULBP4 from the cytoplasm to the cell membrane. Our results uncovered a previously unknown mechanism for HCQ in CML treatment that underlines the ability of HCQ to modulate the immune visibility of CML cells, and pave the way to the development of new combination treatments with HCQ and Vγ9Vδ2 T cells.

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“…Recently, the same effect was observed in some patients with chronic myeloid leukemia (CML) 11 . In clinical use, immunostimulatory effects have been observed during long-term use of dasatinib [12][13][14][15] . The most 1 INSERM, 1082, Poitiers, France.…”

mentioning

confidence: 99%

Innate T-αβ lymphocytes as new immunological components of anti-tumoral “off-target” effects of the tyrosine kinase inhibitor dasatinib

Barbarin

Abdallah

Lefèvre

et al. 2020

Sci Rep

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Kinase inhibitors hold great potential as targeted therapy against malignant cells. Among them, the tyrosine kinase inhibitor dasatinib is known for a number of clinically relevant off-target actions, attributed in part to effects on components of the immune system, especially conventional T-cells and natural killer (NK)-cells. Here, we have hypothesized that dasatinib also influences non-conventional t-αβ cell subsets known for their potential anti-tumoral properties, namely iNKT cells and the distinct new innate CD8 T-cell subset. In mice, where the two subsets were originally characterized, an activated state of iNKT cells associated with a shift toward an iNKT cell Th1-phenotype was observed after dasatinib treatment in vivo. Despite decreased frequency of the total memory CD8 T-cell compartment, the proportion of innate-memory CD8 T-cells and their IFNγ expression in response to an innate-like stimulation increased in response to dasatinib. Lastly, in patients administered with dasatinib for the treatment of BCR-ABL-positive leukemias, we provided the proof of concept that the kinase inhibitor also influences the two innate T-cell subsets in humans, as attested by their increased frequency in the peripheral blood. these data highlight the potential immunostimulatory capacity of dasatinib on innate t-αβ cells, thereby opening new opportunities for chemoimmunotherapy.

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Dasatinib promotes the potential of proliferation and antitumor responses of human γδT cells in a long-term induction ex vivo environment

Abstract: These authors contributed equally to this work. REFERENCES 1 Proud CG. The multifaceted role of mTOR in cellular stress responses. DNA Repair (Amst) 2004; 3: 927-934. 2 Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony.

Cited by 12 publications

References 15 publications

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Innate T-αβ lymphocytes as new immunological components of anti-tumoral “off-target” effects of the tyrosine kinase inhibitor dasatinib

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