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

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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.

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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

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Acknowledgements

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

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.

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Authors and Affiliations

  1. Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Avda. Fuerzas Arnadas s/n, 18014, Granada, Spain

    Paola Montes, Laura N. Campo, Pilar Jiménez, Federico Garrido & Francisco Ruiz-Cabello

  2. Programa de doctorado en Biomedicina, Universidad de Granada, Granada, Spain

    Paola Montes

  3. Servicio de Hematología, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Mónica Bernal, Pilar Garrido, Manuel Jurado & Francisca Hernández

  4. Hospital Universitario San Cecilio, Granada, Spain

    Amanda Rocío González-Ramírez

  5. Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain

    Amanda Rocío González-Ramírez, Federico Garrido & Francisco Ruiz-Cabello

  6. Fundación de Investigación, Biosanitaria Alejandro Otero, FIBAO, Granada, Spain

    Amanda Rocío González-Ramírez

  7. Departamento Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain

    Federico Garrido & Francisco Ruiz-Cabello

Authors
  1. Paola Montes
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  2. Mónica Bernal
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  3. Laura N. Campo
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  4. Amanda Rocío González-Ramírez
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  5. Pilar Jiménez
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  6. Pilar Garrido
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  7. Manuel Jurado
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  8. Federico Garrido
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  9. Francisco Ruiz-Cabello
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  10. Francisca Hernández
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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.

Corresponding author

Correspondence to Francisco Ruiz-Cabello.

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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.

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Montes, P., Bernal, M., Campo, L.N. et al. Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression. Cancer Immunol Immunother 68, 2015–2027 (2019). https://doi.org/10.1007/s00262-019-02420-x

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