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Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression

  • Paola Montes
  • Mónica Bernal
  • Laura N. Campo
  • Amanda Rocío González-Ramírez
  • Pilar Jiménez
  • Pilar Garrido
  • Manuel Jurado
  • Federico Garrido
  • Francisco Ruiz-CabelloEmail author
  • Francisca Hernández
Original Article

Abstract

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.

Keywords

Myelodysplastic syndrome (MDS) Immune microenvironment High molecular risk (HMR) mutations Loss of heterozygosity (LOH) Immune-evasion 

Abbreviations

HLA-I

HLA Class I

HMR

High molecular risk

IPSS

International prognostic scoring system

IPSS-R

International prognostic scoring system revised

LOH HLA

Loss of heterozygosity in the HLA region

LOH

Loss of heterozygosity

MDS del(5q)

MDS with isolated del(5q)

MDS EB

MDS with excess blasts

MDS

Myelodysplastic syndromes

MDSCs

Myeloid derived suppressor cells

MDS-MLD

MDS with multilineage dysplasia

MDS-RS

MLD and ring sideroblasts

MDS-SLD

MDS with single lineage dysplasia

MoAbs

Monoclonal antibodies

NGS

Next-generation sequencing

PB

Peripheral blood

sAML

Secondary acute myeloid leukemia

Notes

Acknowledgements

The authors thank Victoria Calvo and María Corzo for technical assistance.

Author contributions

PM and LNC contributed to the immunophenotypic analysis of the tumor microenvironment. PM and MB contributed to sequencing and data analysis. FH and PG contributed to the diagnosis and classification of patients based on their clinical and hematological characteristics. ARG-R carried out the statistical analyses. PM, MB, PJ, MJ, FG, and FR-C were involved with all aspects of the study’s design and contributed to the manuscript preparation.

Funding

This work was supported by Grants from the Instituto de Salud Carlos III co-financed by FEDER funds (European Union) (PI 16/00752, PI 17/00197) and Junta de Andalucía in Spain (Group CTS-143, PI09/0382). This study is part of the doctoral thesis of Paola Montes, whose pre-doctoral fellowship was partially financed by Abbott, Becton–Dickinson, Beckman Coulter, and the Spanish MDS group.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The procedures with human samples were performed in accordance with the Declaration of Helsinki and the ethical standards of the Research Ethics Committee of Virgen de las Nieves Hospital in Granada, Spain, which approved the project on June 28 2016 (PEIBA code 0713-N-16 and PROYECTO code 555).

Informed consent

Written informed consent was provided by all patients at the time of their diagnosis and by healthy donors at routine analyses during the first few months of the study.

Supplementary material

262_2019_2420_MOESM1_ESM.pdf (600 kb)
Supplementary material 1 (PDF 600 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Paola Montes
    • 1
    • 2
  • Mónica Bernal
    • 3
  • Laura N. Campo
    • 1
  • Amanda Rocío González-Ramírez
    • 4
    • 5
    • 6
  • Pilar Jiménez
    • 1
  • Pilar Garrido
    • 3
  • Manuel Jurado
    • 3
  • Federico Garrido
    • 1
    • 5
    • 7
  • Francisco Ruiz-Cabello
    • 1
    • 5
    • 7
    Email author
  • Francisca Hernández
    • 3
  1. 1.Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las NievesGranadaSpain
  2. 2.Programa de doctorado en BiomedicinaUniversidad de GranadaGranadaSpain
  3. 3.Servicio de Hematología, Hospital Universitario Virgen de las NievesGranadaSpain
  4. 4.Hospital Universitario San CecilioGranadaSpain
  5. 5.Instituto de Investigación Biosanitaria ibs.GRANADAGranadaSpain
  6. 6.Fundación de Investigación, Biosanitaria Alejandro Otero, FIBAOGranadaSpain
  7. 7.Departamento Bioquímica, Biología Molecular e Inmunología IIIUniversidad de GranadaGranadaSpain

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