Immunotherapy in Myeloproliferative Diseases

doi:10.3390/cells9061559

Review

. 2020 Jun 26;9(6):1559.

doi: 10.3390/cells9061559.

Immunotherapy in Myeloproliferative Diseases

Lukas M Braun^{1

2}, Robert Zeiser^{1

3

4

5}

Affiliations

¹ Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
² Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
³ German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁴ Comprehensive Cancer Center Freiburg (CCCF), University of Freiburg, 79106 Freiburg, Germany.
⁵ Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, 79104 Freiburg, Germany.

PMID: 32604862
PMCID: PMC7349594
DOI: 10.3390/cells9061559

Review

Immunotherapy in Myeloproliferative Diseases

Lukas M Braun et al. Cells. 2020.

. 2020 Jun 26;9(6):1559.

doi: 10.3390/cells9061559.

Authors

Lukas M Braun^{1

2}, Robert Zeiser^{1

3

4

5}

Affiliations

¹ Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
² Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
³ German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁴ Comprehensive Cancer Center Freiburg (CCCF), University of Freiburg, 79106 Freiburg, Germany.
⁵ Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, 79104 Freiburg, Germany.

PMID: 32604862
PMCID: PMC7349594
DOI: 10.3390/cells9061559

Abstract

Myeloproliferative diseases, including myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), are driven by genetic abnormalities and increased inflammatory signaling and are at high risk to transform into acute myeloid leukemia (AML). Myeloid-derived suppressor cells were reported to enhance leukemia immune escape by suppressing an effective anti-tumor immune response. MPNs are a potentially immunogenic disease as shown by their response to interferon-α treatment and allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Novel immunotherapeutic approaches such as immune checkpoint inhibition, tumor vaccination, or cellular therapies using target-specific lymphocytes have so far not shown strong therapeutic efficacy. Potential reasons could be the pro-inflammatory and immunosuppressive microenvironment in the bone marrow of patients with MPN, driving tumor immune escape. In this review, we discuss the biology of MPNs with respect to the pro-inflammatory milieu in the bone marrow (BM) and potential immunotherapeutic approaches.

Keywords: AML; CD123; IFNα; JAK2; MDS; MDSCs; MPN; allo-HSCT; immune checkpoint; immune escape; immunotherapy; inflammation; myeloproliferation; tumor vaccination.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
Pro-inflammatory signaling processes driving myeloproliferation and leukemia immune escape in myeloid malignancies. Oncogenic mutations stimulate increased production of ROS and pro-inflammatory cytokines and interleukins. ROS causes DNA damage and favors proliferation of the mutant clone, thereby driving disease progression. Cytokines drive disease progression through elevated Shp2/STAT3 and JAK/STAT signaling. NLRP3-Inflammsome activation results in enhanced myeloproliferation, driving leukemic transformation of myeloproliferative diseases. Increased cytokine signaling in the tumor microenvironment contributes to T-cell exhaustion, reduced T-cell activation, and leukemia immune escape.

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References

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1. Barbui T., Thiele J., Gisslinger H., Kvasnicka H.M., Vannucchi A.M., Guglielmelli P., Orazi A., Tefferi A. The 2016 who classification and diagnostic criteria for myeloproliferative neoplasms: Document summary and in-depth discussion. Blood Cancer J. 2018;8:15. doi: 10.1038/s41408-018-0054-y. - DOI - PMC - PubMed
1. Rampal R., Ahn J., Abdel-Wahab O., Nahas M., Wang K., Lipson D., Otto G.A., Yelensky R., Hricik T., McKenney A.S., et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc. Natl. Acad. Sci. USA. 2014;111:E5401–E5410. doi: 10.1073/pnas.1407792111. - DOI - PMC - PubMed
1. Spivak J.L. Myeloproliferative neoplasms. N. Engl. J. Med. 2017;377:895–896. doi: 10.1056/NEJMra1406186. - DOI - PubMed
1. Vainchenker W., Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129:667–679. doi: 10.1182/blood-2016-10-695940. - DOI - PubMed

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[1] Campbell P.J., Green A.R. The myeloproliferative disorders. N. Engl. J. Med. 2006;355:2452–2466. doi: 10.1056/NEJMra063728. - DOI - PubMed

[2] Campbell P.J., Green A.R. The myeloproliferative disorders. N. Engl. J. Med. 2006;355:2452–2466. doi: 10.1056/NEJMra063728. - DOI - PubMed

[3] Barbui T., Thiele J., Gisslinger H., Kvasnicka H.M., Vannucchi A.M., Guglielmelli P., Orazi A., Tefferi A. The 2016 who classification and diagnostic criteria for myeloproliferative neoplasms: Document summary and in-depth discussion. Blood Cancer J. 2018;8:15. doi: 10.1038/s41408-018-0054-y. - DOI - PMC - PubMed

[4] Barbui T., Thiele J., Gisslinger H., Kvasnicka H.M., Vannucchi A.M., Guglielmelli P., Orazi A., Tefferi A. The 2016 who classification and diagnostic criteria for myeloproliferative neoplasms: Document summary and in-depth discussion. Blood Cancer J. 2018;8:15. doi: 10.1038/s41408-018-0054-y. - DOI - PMC - PubMed

[5] Rampal R., Ahn J., Abdel-Wahab O., Nahas M., Wang K., Lipson D., Otto G.A., Yelensky R., Hricik T., McKenney A.S., et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc. Natl. Acad. Sci. USA. 2014;111:E5401–E5410. doi: 10.1073/pnas.1407792111. - DOI - PMC - PubMed

[6] Rampal R., Ahn J., Abdel-Wahab O., Nahas M., Wang K., Lipson D., Otto G.A., Yelensky R., Hricik T., McKenney A.S., et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc. Natl. Acad. Sci. USA. 2014;111:E5401–E5410. doi: 10.1073/pnas.1407792111. - DOI - PMC - PubMed

[7] Spivak J.L. Myeloproliferative neoplasms. N. Engl. J. Med. 2017;377:895–896. doi: 10.1056/NEJMra1406186. - DOI - PubMed

[8] Spivak J.L. Myeloproliferative neoplasms. N. Engl. J. Med. 2017;377:895–896. doi: 10.1056/NEJMra1406186. - DOI - PubMed

[9] Vainchenker W., Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129:667–679. doi: 10.1182/blood-2016-10-695940. - DOI - PubMed

[10] Vainchenker W., Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129:667–679. doi: 10.1182/blood-2016-10-695940. - DOI - PubMed

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Immunotherapy in Myeloproliferative Diseases

Affiliations

Immunotherapy in Myeloproliferative Diseases

Authors

Affiliations

Abstract

Conflict of interest statement

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