Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Create Dendritic Cells of Leukemic Origin from AML Patients’ Whole Blood and Whole Bone Marrow That Mediate Antileukemic Processes after Mixed Lymphocyte Culture
Abstract
:1. Introduction
1.1. Acute Myeloid Leukemia
1.2. The Physiologic and Leukemic Bone Marrow Niche
1.3. Standard Treatment and Advances in AML Therapy
1.4. DC/DCleu-Based Therapy
1.5. Aim of the Study
- Composition of immune cells in uncultured (as well as after mixed lymphocyte culture (MLC) with Kit-M-treated vs. untreated) WB and WBM
- DC (subsets) from Kit-M-treated vs. untreated leukemic WB and WBM
- Platelet counts in WB and WBM DC culture supernatants under the influence of Kit-M vs. GM-CSF
- (Leukemia-specific/antileukemic) immunoreactive cells (activating/inhibitory cells of the adaptive and innate immune system: NK-, CIK-, iNKT- and T-cell subtypes) were specified using degranulation (DEG), intracellular cytokine (INCYT) as well as cytotoxicity (CTX) assays in uncultured WB and WBM and after MLC with Kit-M-treated vs. untreated WB and WBM
- Differences of results obtained in WB vs. WBM
- Correlation analyses of ex vivo generated data with patients’ allocation to clinical risk groups
2. Results
2.1. Uncultured WB and WBM
2.1.1. Composition of T and Innate Immune Cells in Uncultured Leukemic WB and WBM
2.1.2. Composition of (Leukemia-Specific) Degranulating or Intracellularly IFNγ- (and TNFα-) Producing Immunoreactive Cells in Uncultured WB and WBM
2.2. Effects of Kit-M on the Generation of Mature DC/DCleu from Leukemic WB and WBM
2.3. Effects of Kit-M-Treated WB and WBM on Immunoreactive Cells before and after T Cell-Enriched Mixed Lymphocyte Culture (MLC)
2.4. Effects of Kit-M-Treated WB and WBM on the Degranulation Activity of Immunoreactive Cells after MLC
2.5. Effects of Kit-M-Treated WB and WBM on the Intracellular IFNγ (and TNFα) Production of Immunoreactive Cells after MLC
2.6. Effects of Kit-M-Treated WB and WBM on the Anti-Leukemic, Blastolytic Functionality after MLC
2.7. Correlation of Results with Patients’ Allocation to First Diagnosis and to Relapse after SCT
2.8. Correlation of Antileukemic Cytotoxicity with Patients’ Allocation to Risk Groups
2.9. Correlation of Antileukemic Cytotoxicity with Patients’ Allocation to Response to Induction Chemotherapy
2.10. Effects of Kit-M-Treated WB and WBM on Platelet Counts
3. Discussion
3.1. WBM-the Immunosuppressive Leukemic Microenvironment
3.2. DC-Based Immunotherapy
3.3. Composition of Uncultured WB and WBM
3.4. Generation of (Mature) DC/DCleu in Kit-M-Treated WB and WBM
3.5. Provision of Immunoreactive Cells after MLC in Kit-M-Treated WB and WBM
3.6. Enhanced Degranulation Activity of T Cells after MLC in Kit-M-Treated WB and WBM
3.7. Enhanced IFNγ Production of T Cells after MLC in Kit-M-Treated WB and WBM
3.8. Improved Blastolytic Activity after MLC in Kit-M-treated WB and WBM
3.9. Correlation of Results with Patients’ Allocation to First Diagnosis and to Relapse after SCT
3.10. Influence of Kit-M or GM-CSF on Platelet Counts in WB and WBM
4. Materials and Methods
4.1. Sample Collection
4.2. Patients’ Characteristics
4.3. Flow Cytometry
4.4. Sample Preparation
4.5. Dendritic Cell Culture
4.6. T Cell-Enriched Mixed Lymphocyte Culture (MLC)
4.7. Degranulation Assay (DEG)
4.8. Intracellular Cytokine Assay (INTCYT)
4.9. Cytotoxicity Fluorolysis Assay (CTX)
4.10. Platelet Counts
4.11. Statistical Methods
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Stage | Patient No. | Age at Sampling/Sex | FAB/WHO Classification | ELN (2017)-Risk-Stratification | Cyto-, Molecular Genetics | Blast Phenotype (CD) | IC in WB/WBM (%) * | Response to Induction Chemotherapy | Experiments Conducted with WB | Experiments Conducted with WBM |
---|---|---|---|---|---|---|---|---|---|---|
First Diagnosis | 1615 | 78/F | sAML | Intermediate | IDH1, ASXL1, JAK2, SRSF2 | 34, 117, 13 | 53/65 | no | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, CTX |
1618 | 63/M | pAML/M1 | Favorable | NPM1 | 117, 33, 13, 15 | 10/7 | yes | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, CTX | |
1620 | 61/F | sAML | Adverse | t(2;3)(p23;q26), del (7)(q21), del(7)(q31), MECOM rearrangement, ASXL1, RUNX1 | 34, 117, 33, 4 | 4/12 | no | DC, MLC, Deg (UC), InCyt (UC), CTX | DC, MLC, CTX | |
1621 | 71/M | sAML | Adverse | TP53, ASXL1, SRSF2, SETPBP1, KRAS | 34, 117, 5, 13 | 18/24 | no | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, CTX | |
1624 | 77/F | sAML | Adverse | monosomy 7, der(7)t(1;7), der (2)t(2;3), del(7)(q31), ampl(3q26), IDH2, STAG2, DNMT3A, MPL, NRAS, SRSF2 | 34, 117, 13 | 30/32 | yes | DC, MLC, Deg (UC), InCyt (UC), CTX | DC, MLC, CTX | |
1630 | 29/M | pAML | Favorable | FLT3-TKD, NPM1, PTPN11 | 34, 117, 13, 33, 15, 64, 65 | 20/27 | yes | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (C), InCyt (C), CTX | |
1638 | 68/M | sAML | Adverse | del(5)(q31), TP53, RUNX1, RUNX1T1 | 34, 117, 33, 13, 56, 4 | 60/54 | no | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | |
1642 | 63/F | sAML | Adverse | IDH2, complex aberrant | 34, 117, 33, 13 | 1/19 | yes | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | |
1643 | 68/M | pAML | Favorable | NPM1, IDH2 | 117, 33, 64, 13 | 23/39 | no | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | |
1645 | 58/F | pAML | Favorable | IDH2, NPM1 | 117, 33, 56 | 36/47 | yes | DC, MLC, Deg (UC), InCyt (UC) | DC, MLC, Deg (UC), InCyt (UC) | |
Persisting Disease | 1601 | 75/F | sAML | Adverse | none detected | 34, 117, 33, 13 | 61/49 | DC, MLC, Deg (UC), InCyt (UC), CTX | DC, MLC, CTX | |
Chimerism (%) | ||||||||||
Relapse After Stem Cell Transplantation | 1628 | 22/F | tAML/M5 | RUNX1, WT1, FLT3-ITD, KMT2A-PTD | 34, 117, 65, 33, 56, 64 | 3/31 | 77 | DC, Deg (UC), InCyt (UC) | DC | |
1640 | 73/F | pAML | del(9q), NMP1, IDH2, WT1, DNMT3A | 34, 117, 33, 13, 7 | <1/<1 | 56 | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | ||
1641 | 64/F | tAML | dup(13)(q12q33), DLEU signal, FLT3-ITD, EZH2, WT1 | 34, 117, 33, 13, 64, 65, 15 | 6/16 | 62 | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | ||
1650 | 64/F | AML-MRC | RUNX1, BCOR, KMT2A-PTD, TP53 | 34, 117, 13 | 3/8 | 86 | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, Deg (UC), InCyt (UC) | ||
1654 | 71/M | pAML/M2 | der(16)t(16;17), NPM1 | 117, 56, 13, 34 | 3/3 | 97 | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | ||
1656 | 42/F | pAML | MECOM rearrangement, complex aberrant, PTPN11 | 34, 117, 33, 56, 13 | 7/14 | 86 | DC, MLC, Deg (UC, C), InCyt (UC, C), CTX | DC, MLC, Deg (C), InCyt (C), CTX |
Cell Type | Name of Subgroups | Abbreviation of Subgroups | Surface Marker | Referred to | Abbreviation | Reference |
---|---|---|---|---|---|---|
Subtypes of blasts and DC | ||||||
Blast cells | Leukemic blasts | Bla | Bla+ (e.g., CD34+, CD177+) | WB or WBM | Bla/WB or/WBM | [32] |
Proliferating blasts | Blaprol-CD71 | Bla+DC−CD71+ | Bla | Blaprol-CD71/Bla | [33] | |
Proliferating blasts | Blaprol-Ipo38 | Bla+DC−Ipo38+ | Bla | Blaprol-Ipo38/Bla | [33] | |
Dendritic cells | Dendritic cells | DC | DC+ (CD80+, CD206+) | WB or WBM | DC/WB or/WBM | [35] |
Leukemia derived DC | DCleu | DC+Bla+ | WB or WBM | DCleu/WB or/WBM | [35] | |
Bla | DCleu/Bla | |||||
Mature DC | DCmat | DC+CD197+ | WB or WBM | DCmat/WB or/WBM | [35] | |
Mature DCleu | DCleu-mat | DC+CD197+Bla+ | WB or WBM | DCleu-mat/WB or/WBM | [35] | |
Bla | DCleu-mat/Bla | [35] | ||||
Subtypes of Immune Reactive Cells | ||||||
T cells | CD3+ pan T cells | CD3+ | CD3+ | cells | CD3+/cells | [36] |
CD4+coexpressing T cells | CD3+CD4+ | CD3+CD4+ | CD3+ | CD3+CD4+/CD3+ | [36] | |
CD8+coexpressing T cells | CD3+CD8+ | CD3+CD8+ | CD3+ | CD3+CD8+/CD3+ | [36] | |
Proliferating T cells-early | Tprol-early | CD3+CD69+ | CD3+ | Tprol-early/CD3+ | [36] | |
Non-naive T cells | Tnon-naive | CD3+CD45RO+ | CD3+ | Tnon-naive/CD3+ | [34] | |
Effector (memory) T cells | Tem/eff | CD3+CD45RO+CD197− | CD3+ | Tem/eff/CD3+ | [34] | |
Central (memory) T cells | Tcm | CD3+CD45RO+CD197+ | CD3+ | Tcm/CD3+ | [34] | |
CD137+ coexpressing T cells | CD3+CD137+ | CD3+CD137+ | CD3+ | CD3+CD137+/CD3+ | [63] | |
Integrinβ7+ coexpressing T cells | CD3+β7+ | CD3+Integrinβ7+ | CD3+ | CD3+β7+/CD3+ | [46] | |
TCRγδ+ coexpressing T cells | CD3+TCRγδ | CD3+TCRγδ+ | CD3+ | CD3+TCRγδ+/CD3+ | [46] | |
CD152+ coexpressing T cells | CD3+CD152+ | CD3+CD152+ | CD3+ | CD3+CD152+/CD3+ | [52] | |
Regulatory T cells | CD4+Treg | CD3+CD4+CD25+CD127low | CD3+CD4+ | CD4+Treg/CD4+ | [48] | |
Natural killer cells | CD3−CD56+NK cells | NK | CD3−CD56+ | Cells | NK/cells | [53] |
Cytokine induced killer cells | CD3+CD56+ CIK cells | CIK | CD3+CD56+ | Cells | CIK/cells | [53] |
Invariant natural killer T cells | 6B11+ iNKT cells | iNKT | 6B11+ | Cells | iNKT/cells | [53] |
CD3+ coexpressing 6B11+ iNKT cells | CD3+iNKT | CD3+6B11+ | 6B11+ | CD3+iNKT/iNKT | [53] | |
Subtypes of different degranulating (CD107a+) cells as evaluated by flow cytometry | ||||||
T cells | CD3+ pan T cells | CD3+107a+ | CD107a+CD3+ | CD3+ | CD3+107a+/CD3+ | [64] |
Non-naive T cells | Tnon-naive107a+ | CD107a+CD3+CD45RO+ | Tnon-naive | Tnon-naive107a+/Tnon-naive | [64] | |
Effector (memory) T cells | Tem/eff107a+ | CD107a+CD3+CD45RO+CD197− | Tem/eff | Tem/eff107a+/Tem/eff | [64] | |
Central (memory) T cells | Tcm107a+ | CD107a+CD3+CD45RO+CD197+ | Tcm | Tcm107a+/Tcm | [64] | |
Integrinβ7+ coexpressing T cells | CD3+β7+107a+ | CD107a+CD3+Integrinβ7+ | CD3+ | CD3+β7+107a+/CD3+ | [46] | |
TCRγδ+ coexpressing T cells | CD3+TCRγδ+107a+ | CD107a+CD3+TCRγδ+ | CD3+TCRγδ+ | CD3+TCRγδ+107a+/CD3+ TCRγδ+ | [65] | |
Regulatory T cells | CD4+Treg107a+ | CD107a+CD4+CD25+CD127low | CD4+Treg | CD4+Treg107a+/CD4+Treg | [48] | |
NK cells | CD3−CD56+NK cells | NK107a+ | CD107a+CD3−CD56+ | NKcell | NK107a+/NK | [64] |
CIK cells | CD3+CD56+ CIK cells | CIK107a+ | CD107a+CD3+CD56+ | CIKcell | CIK107a+/CIK | [64] |
Subtypes of different intracellularly IFNγ or TNFα-producing cells as evaluated by flow cytometry | ||||||
T cells | CD3+ pan T cells | CD3+IFNγ/TNFα | IFNγ+/TNFα+CD3+ | CD3+ | CD3+IFNγ/TNFα/CD3+ | [34] |
CD4+-coexpressing T cells | CD3+CD4+IFNγ/TNFα | IFNγ+/TNFα+CD3+CD4+ | CD3+CD4+ | CD3+CD4+IFNγ/TNFα/CD3+CD4+ | [34] | |
CD8+-coexpressing T cells | CD3+CD8+IFNγ/TNFα | IFNγ+/TNFα+CD3+CD8+ | CD3+CD8+ | CD3+CD4−IFNγ/TNFα/CD3+CD8+ | [34] | |
Non-naive T cells | Tnon-naive IFNγ/TNFα | IFNγ+/TNFα+CD3+CD45RO+ | Tnon-naive | Tnon-naive IFNγ/TNFα/Tnon-naive | [34] | |
Effector (memory) T cells | Tem/eff IFNγ/TNFα/Tem/eff | IFNγ+/TNFα+CD3+CD45RO+CD197− | Tem/eff | Tem/eff IFNγ/TNFα/Tem/eff | [34] | |
Central (memory) T cells | Tcm IFNγ/TNFα | IFNγ+/TNFα+CD3+CD45RO+CD197+ | Tcm | Tcm IFNγ/TNFα/Tcm | [34] | |
Integrinβ7+ coexpressing T cells | CD3+β7+IFNγ/TNFα | IFNγ+/TNFα+CD3+β7+ | CD3+β7+ | CD3+β7+IFNγ/TNFα/CD3+β7+ | [46] | |
NK cells | CD3−CD56+NK cells | CD3−CD56+IFNγ/TNFα | IFNγ+/TNFα+CD3−CD56+ | NK | NKIFNγ/TNFα/NK | [34] |
CIK cells | CD3+CD56+ CIK cells | CIIFNγ/TNFα | IFNγ+/TNFα+CD3+CD56+ | CIK | CIKIFNγ/TNFα/CIK | [34] |
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Unterfrauner, M.; Rejeski, H.A.; Hartz, A.; Bohlscheid, S.; Baudrexler, T.; Feng, X.; Rackl, E.; Li, L.; Rank, A.; Filippini Velázquez, G.; et al. Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Create Dendritic Cells of Leukemic Origin from AML Patients’ Whole Blood and Whole Bone Marrow That Mediate Antileukemic Processes after Mixed Lymphocyte Culture. Int. J. Mol. Sci. 2023, 24, 17436. https://doi.org/10.3390/ijms242417436
Unterfrauner M, Rejeski HA, Hartz A, Bohlscheid S, Baudrexler T, Feng X, Rackl E, Li L, Rank A, Filippini Velázquez G, et al. Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Create Dendritic Cells of Leukemic Origin from AML Patients’ Whole Blood and Whole Bone Marrow That Mediate Antileukemic Processes after Mixed Lymphocyte Culture. International Journal of Molecular Sciences. 2023; 24(24):17436. https://doi.org/10.3390/ijms242417436
Chicago/Turabian StyleUnterfrauner, Marianne, Hazal Aslan Rejeski, Anne Hartz, Sophia Bohlscheid, Tobias Baudrexler, Xiaojia Feng, Elias Rackl, Lin Li, Andreas Rank, Giuliano Filippini Velázquez, and et al. 2023. "Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Create Dendritic Cells of Leukemic Origin from AML Patients’ Whole Blood and Whole Bone Marrow That Mediate Antileukemic Processes after Mixed Lymphocyte Culture" International Journal of Molecular Sciences 24, no. 24: 17436. https://doi.org/10.3390/ijms242417436