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In silico transcriptomic mapping of integrins and immune activation in Basal-like and HER2+ breast cancer

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Abstract

Purpose

Integrins, transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions, have been linked to several cancer-associated features. A less explored function of integrins in cancer is their role in leukocyte homing and activation. Understanding their relationship with immune cell infiltrates and immune checkpoints is an area of interest in cancer research.

Methods

The expression of 33 different integrins was evaluated in relation with breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to assess the association of the identified integrin genes with immune cell infiltration, and the TCGA and METABRIC studies to assess correlations between integrin gene expression and genomic signatures of immune activation.

Results

We identified 7 genes coding for integrin α and β subunits, i.e., ITGA4, ITGB2, ITGAX, ITGB7, ITGAM, ITGAL and ITGA8, which predict a favorable prognosis in Basal-like and HER2+ breast cancers. Their expression positively correlated with the presence of immune cell infiltrates within the tumor (dendritic cells, CD4+ T-cells, neutrophils, CD8+ T-cells and B-cells), with markers of T-cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast, we found that genes coding for integrins that predicted a detrimental outcome (IBSP, ITGB3BP, ITGB6, ITGB1 and ITGAV) were not associated with any of these parameters.

Conclusions

We identified an integrin signature composed of 7 genes with potential to recognize immune infiltrated and activated Basal-like and HER2+ breast cancers with a favorable prognosis.

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Data availability

Data are available upon reasonable request.

Abbreviations

APC:

antigen presenting cell

CI:

confidence interval

CTL:

cytotoxic T lymphocyte

DC:

dendritic cells

ECM:

extracellular matrix

FDR:

false discovery rate

HR:

hazard ratio

ICAM:

intercellular adhesion molecule

IFN:

Interferon

KM:

Kaplan-Meier

LAD:

leukocyte adhesion deficiency

LFA:

leukocyte function-associated antigen 1

NK:

natural killer

OS:

overall survival

P:

p-value

PD-1:

programmed cell death protein-1

PD-L1:

programmed cell death protein ligand-1

RFS:

relapse-free survival

TGF-β:

transforming growth factor β

TIMER:

Tumor Immune Estimation Resource

VCAM-1:

vascular intercellular adhesion molecule 1

VLA-4:

very late antigen 4

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Funding

This work was supported by the Instituto de Salud Carlos III (PI19/00808), ACEPAIN, Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to A. Ocaña) and the Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to A. Pandiella). Our laboratories receive support from the European Community through the regional development funding program (FEDER). BG was supported by a 2018 − 2.1.17-TET-KR-00001 grant and by the Higher Education Institutional Excellence Programme (2020 − 4.1.1.-TKP2020) of the Ministry for Innovation and Technology of Hungary, within the framework of the Bionic thematic programme of the Semmelweis University.

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Author notes

  1. Katerin Rojas and Mariona Baliu-Piqué contributed equally to this work.

Authors and Affiliations

  1. Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria (IdISSC) and CIBERONC, Calle Del Prof Martín Lagos, s/n, 28040, Madrid, Spain

    Katerin Rojas, Mariona Baliu-Piqué, Aránzazu Manzano, Cristina Saiz-Ladera, Vanesa García-Barberán, Pedro Pérez-Segura & Alberto Ocana

  2. Translational Research Unit, Translational Oncology Laboratory, Albacete University Hospital, Albacete, Spain

    Francisco J. Cimas

  3. Centro Regional de Investigaciones Biomedicas, Castilla-La Mancha University (CRIB-UCLM), Albacete, Spain

    Francisco J. Cimas

  4. Instituto de Biología Molecular y Celular del Cáncer and CIBERONC, CSIC , Salamanca, Spain

    Atanasio Pandiella

  5. Department of Bioinformatics, Semmelweis University, Budapest, Hungary

    Balázs Győrffy

  6. 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary

    Balázs Győrffy

  7. TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary

    Balázs Győrffy

Authors
  1. Katerin Rojas
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  2. Mariona Baliu-Piqué
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  3. Aránzazu Manzano
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  4. Cristina Saiz-Ladera
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  5. Vanesa García-Barberán
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  9. Balázs Győrffy
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  10. Alberto Ocana
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Contributions

K.R., M.B.P. and A.O. conceived and designed the study. K.R., M.B.P., A.M., C.S.L and B.G. searched the data and performed the analyses. M.B.P., A.O., K.R., A.M., C.S.L, V.G.B, F.C., P.P.S, A.P. and B.G wrote the manuscript. All authors reviewed, included modifications and approved the final version of the manuscript.

Corresponding author

Correspondence to Alberto Ocana.

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Conflict of interest

A.O. receives funding from Entrechem, travel expenses from Merck and advisory board fees from Daiichi Sankyo. P.P.S. receives funding from Merck and MSD. A.P. receives consultancy fees from Daiichi Sankyo.

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This study does not involve human participants or experimental animal models.

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Rojas, K., Baliu-Piqué, M., Manzano, A. et al. In silico transcriptomic mapping of integrins and immune activation in Basal-like and HER2+ breast cancer. Cell Oncol. 44, 569–580 (2021). https://doi.org/10.1007/s13402-020-00583-9

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