Katerin Rojas1, Mariona Baliu-Piqué1, Aránzazu Manzano1, Cristina Saiz-Ladera1, Vanesa García-Barberán1, Francisco J Cimas2,3, Pedro Pérez-Segura1, Atanasio Pandiella4, Balázs Győrffy5,6,7, Alberto Ocana8. 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. 2. Translational Research Unit, Translational Oncology Laboratory, Albacete University Hospital, Albacete, Spain. 3. Centro Regional de Investigaciones Biomedicas, Castilla-La Mancha University (CRIB-UCLM), Albacete, Spain. 4. Instituto de Biología Molecular y Celular del Cáncer and CIBERONC, CSIC , Salamanca, Spain. 5. Department of Bioinformatics, Semmelweis University, Budapest, Hungary. 6. 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary. 7. TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary. 8. 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. alberto.ocana@salud.madrid.org.
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.
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.
Authors: João C D Muzzi; Jessica M Magno; Milena A Cardoso; Juliana de Moura; Mauro A A Castro; Bonald C Figueiredo Journal: Front Endocrinol (Lausanne) Date: 2021-06-14 Impact factor: 5.555