Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia

Stephanie G. Craig, Matthew P Humphries, Matthew Alderdice, Victoria Bingham, Susan D. Richman, Maurice B. Loughrey, Helen G Coleman, Amelie Viratham-Pulsawatdi, Kris McCombe, Graeme I. Murray, Andrew Blake, Enric Domingo, James Robineau, Louise Brown, David Fisher, Matthew T. Seymour, Phil Quirke, Peter Bankhead, Stephen McQuaid, Mark LawlerDarragh G. McArt, Tim S. Maughan, Jacqueline A James, Manuel Salto-Tellez* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)
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BACKGROUND: Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy.

METHODS: Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology.

RESULTS: Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression).

CONCLUSIONS: Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.

Original languageEnglish
Pages (from-to)1280-1288
Number of pages9
JournalBritish Journal of Cancer
Early online date20 Jul 2020
Publication statusPublished - 13 Oct 2020

Bibliographical note

PQ is a National Institute of Health Research Senior Investigator.
The funders had no role in study design, collection, data analysis, or interpretation of the data. This study was supported by a Cancer Research UK Accelerator grant and carried out in collaboration with the stratified medicine consortium in colorectal cancer (S:CORT) which is jointly funded by the Medical Research Council and Cancer Research UK.
Data availability
The data are held within the Northern Ireland Biobank and the stratified medicine consortium in colorectal cancer (S:CORT), respectively, and are available on application.


  • Cancer microenvironment
  • colorectal cancer
  • tumour biomarkers


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