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Inclusion of BLIMP-1+ effector regulatory T cells improves the Immunoscore in a cohort of New Zealand colorectal cancer patients: a pilot study

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Abstract

Analysis of tumour-infiltrating T cells in colorectal cancer can predict disease-free survival. The Immunoscore, obtained by quantifying tumour-infiltrating CD3+ and CD8+ T cells, may improve current staging. Effector regulatory T cells are a potently suppressive subset in mice and, while present in human colorectal cancer, their role in patient outcome is unknown. Immunofluorescence was used to analyse immune cell infiltrates in patients with early (stage II) colorectal cancer with (n = 13) and without (n = 19) recurrent disease. CD3 and CD8 were used for the Immunoscore; FOXP3, BLIMP-1 and CD3 to identify effector regulatory T cells. Patients with high Immunoscores had increased disease-free survival compared to patients with low Immunoscores (Log-rank test p < 0.01). Prediction of outcome was further improved by stratifying patients with a low Immunoscore according to CD3+FOXP3+BLIMP-1+ cell infiltration at the invasive margin. Patients with a low Immunoscore and high infiltrate of CD3+FOXP3+BLIMP-1+ cells tended to have better disease-free survival than patients with low Immunoscore and low infiltrate of CD3+FOXP3+BLIMP-1+ cells. Patients with a high Immunoscore had better disease-free survival than patients with a low Immunoscore and low infiltrate of CD3+ FOXP3+ BLIMP-1+ cells (Log-rank test p < 0.001). These results indicate that tumour infiltration with effector regulatory T cells improves the prognostic value of the Immunoscore and implies that these cells may play a role in colorectal cancer patient outcome.

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Abbreviations

AJCC:

American Joint Committee on Cancer

BLIMP-1:

B lymphocyte-induced maturation protein-1

CRC:

Colorectal cancer

FFPE:

Formalin-fixed, paraffin-embedded

HPF:

High power field

ICC:

Intraclass correlation coefficient

IRIISS:

Independent Research Institute Infrastructure Support Scheme

IS:

Immunoscore

NHMRC:

National Health and Medical Research Council

Treg:

Regulatory T cell

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Acknowledgements

We wish to thank all patients who participated in this study. In addition, we thank Tania Slatter and Tim Hodgson for pathology support and Mandy Fisher and the Histology Unit of Otago University for sample processing. We thank Andrew Gray, Mik Black and Josie Athens for statistical advice and Edward Taylor for establishing laboratory protocols. Thank you to Stephen L Nutt and Lynn M Corcoran (The Walter and Eliza Hall Institute of Medical Research) for providing the BLIMP-1 antibody.

This study was funded by the Genesis Oncology Trust and Lotteries Health New Zealand. Kirsten Ward-Hartstonge was supported by the Todd Foundation for Excellence, a Brenda Shore Award for Women and a PhD scholarship from Lotteries Health New Zealand. Erika Cretney was supported by a National Health and Medical Research Council (NHMRC) Fellowship and project grant #1047313. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS. Adam Girardin received travel support for techniques from the Maurice and Phyllis Paykel Trust.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Otago, PO Box 56, Dunedin, 9054, New Zealand

    Kirsten A. Ward-Hartstonge, Timothy R. McCulloch, Ann-Kristin Kamps, Adam Girardin & Roslyn A. Kemp

  2. Department of Surgical Sciences, University of Otago, PO Box 56, Dunedin, 9054, New Zealand

    John L. McCall & Fran M. Munro

  3. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia

    Erika Cretney

  4. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia

    Erika Cretney

Authors
  1. Kirsten A. Ward-Hartstonge
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  2. John L. McCall
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Correspondence to Roslyn A. Kemp.

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Ward-Hartstonge, K.A., McCall, J.L., McCulloch, T.R. et al. Inclusion of BLIMP-1+ effector regulatory T cells improves the Immunoscore in a cohort of New Zealand colorectal cancer patients: a pilot study. Cancer Immunol Immunother 66, 515–522 (2017). https://doi.org/10.1007/s00262-016-1951-1

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