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

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

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Abbreviations

CCL:

Chemokine (C–C motif) ligand

CM:

Conditioned media

CRC:

Colorectal cancer,

CRLM:

Colorectal liver metastases,

CXCL:

Chemokine (C-X-C motif) ligand

DPP4:

Dipeptidyl peptidase-4

HPF:

High-powered field

LIF:

Leukemia inhibitory factor

MIF:

Macrophage migration inhibitory factor

NLR:

Neutrophil-to-lymphocyte ratio

PMN:

Polymorphonuclear leukocytes

VEGF:

Vascular endothelial growth factor

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Funding

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.

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Author notes

  1. Justin G. Geoghegan, Elizabeth J. Ryan, and Cliona O’Farrelly have contributed equally to this work.

Authors and Affiliations

  1. National Liver Unit, St. Vincent’s Hospital, Elm Park, Dublin 4, Ireland

    Fiona Hand, Donal Maguire, Emir Hoti, Niamh Nolan & Justin G. Geoghegan

  2. School of Biochemistry and Immunology and School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, 154-160 Pearse Street, Dublin 2, D02 R590, Ireland

    Fiona Hand, Cathal Harmon & Cliona O’Farrelly

  3. Centre for Colorectal Disease, School of Medicine, University College Dublin and St. Vincent’s Hospital, Elm Park, Dublin 4, Ireland

    Louise A. Elliott, Francesco Caiazza, Aonghus Lavelle & Elizabeth J. Ryan

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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.

Corresponding author

Correspondence to Cliona O’Farrelly.

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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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Hand, F., Harmon, C., Elliott, L.A. et al. Depleted polymorphonuclear leukocytes in human metastatic liver reflect an altered immune microenvironment associated with recurrent metastasis. Cancer Immunol Immunother 67, 1041–1052 (2018). https://doi.org/10.1007/s00262-018-2149-5

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