Cancer Immunology, Immunotherapy

, Volume 67, Issue 7, pp 1041–1052 | Cite as

Depleted polymorphonuclear leukocytes in human metastatic liver reflect an altered immune microenvironment associated with recurrent metastasis

  • Fiona Hand
  • Cathal Harmon
  • Louise A. Elliott
  • Francesco Caiazza
  • Aonghus Lavelle
  • Donal Maguire
  • Emir Hoti
  • Niamh Nolan
  • Justin G. Geoghegan
  • Elizabeth J. Ryan
  • Cliona O’Farrelly
Original Article



Hepatic immunity, normally protective against neoplasia, is subverted in colorectal liver metastasis (CRLM). Here, we compare the inflammatory microenvironment of CRLM-bearing liver tissue to donor liver.


Twenty-five patients undergoing resection for CRLM were recruited, 13 of whom developed intrahepatic recurrence within 18 months. Biopsies were obtained from tumour and normal liver tissue adjacent to and distal from, the tumour. Donor liver biopsies were obtained during transplantation. Biopsies were cultured and conditioned media (CM) screened for 102 inflammatory mediators. Twelve of these were validated by Luminex assay. Transwell assays measured cancer cell chemotaxis. Polymorphonuclear leukocytes (PMN) and lymphocytes were quantified in H&E sections.


Fewer periportal tissue-resident PMN were present in metastatic liver compared to donor liver. Patients with the fewest PMN in liver tissue distal to their tumour had a shorter time to intrahepatic recurrence (P < 0.001). IL-6, CXCL1, CXCL5, G-CSF, GM-CSF, VEGF, LIF, and CCL3 were higher in liver-bearing CRLM compared to donor tissue. Consequently, cancer cells migrated equally towards CM of all regions of metastatic liver but not towards donor liver CM.


The local inflammatory environment may affect both immune cell infiltration and cancer cell migration contributing to recurrence following resection for CRLM.


Leukocytes Colorectal liver metastases Immune microenvironment Tumour progression 



Chemokine (C–C motif) ligand


Conditioned media


Colorectal cancer,


Colorectal liver metastases,


Chemokine (C-X-C motif) ligand


Dipeptidyl peptidase-4


High-powered field


Leukemia inhibitory factor


Macrophage migration inhibitory factor


Neutrophil-to-lymphocyte ratio


Polymorphonuclear leukocytes


Vascular endothelial growth factor


Author contributions

FH: study design and conception, data collection, analysis and interpretation, drafted, reviewed, edited, and approved manuscript. CH: study design and conception, data analysis and interpretation, drafted, and approved manuscript. LAE: data collection and analysis, and reviewed and approved manuscript. FC: data collection and analysis, and reviewed and approved manuscript. AL: data analysis, and reviewed and approved manuscript. DM: provided clinical samples, and reviewed and approved manuscript. EH: provided clinical samples, and reviewed and approved manuscript. NN: data collection and analysis, and reviewed and approved manuscript. JGG: study design and conception, provided clinical samples, and reviewed and approved manuscript. EJR: study conception, design and supervision, data collection, and analysis, and drafted and approved manuscript. CO’F: study conception, design and supervision, and drafted and approved manuscript.


This work was supported by grants from the Health Research Board of Ireland (RP 2008/189) to C.O’Farrelly and HRA-POR-2013-281 to E.J. Ryan and a Science Foundation Ireland Investigator Award (132/IA/1667) to C. O’Farrelly.

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interest.

Ethical approval and ethical standards

All protocols were approved by St. Vincent’s University Hospital Ethics Committee in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.

Informed consent

Informed consent was provided by all patients prior to undergoing resection. A patient information leaflet was provided and all queries addressed by F. Hand before consent was provided. Where donor liver was obtained, informed consent was given by the donor’s family prior to sampling. Donor families were approached by a dedicated transplant coordinator. All protocols and study information were provided to the family prior to consenting.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Fiona Hand
    • 1
    • 2
  • Cathal Harmon
    • 2
  • Louise A. Elliott
    • 3
  • Francesco Caiazza
    • 3
  • Aonghus Lavelle
    • 3
  • Donal Maguire
    • 1
  • Emir Hoti
    • 1
  • Niamh Nolan
    • 1
  • Justin G. Geoghegan
    • 1
  • Elizabeth J. Ryan
    • 3
  • Cliona O’Farrelly
    • 2
  1. 1.National Liver UnitSt. Vincent’s HospitalDublin 4Ireland
  2. 2.School of Biochemistry and Immunology and School of Medicine, Trinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland
  3. 3.Centre for Colorectal Disease, School of MedicineUniversity College Dublin and St. Vincent’s HospitalDublin 4Ireland

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