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 Lawler; Darragh G. McArt; Tim S.  Maughan; Jacqueline A James; Manuel Salto-Tellez

doi:10.1038/s41416-020-0985-5

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 journal › Article › peer-review

36 Citations (Scopus)

5 Downloads (Pure)

Abstract

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 language	English
Pages (from-to)	1280-1288
Number of pages	9
Journal	British Journal of Cancer
Volume	123
Early online date	20 Jul 2020
DOIs	https://doi.org/10.1038/s41416-020-0985-5
Publication status	Published - 13 Oct 2020

Keywords

Cancer microenvironment
colorectal cancer
tumour biomarkers
MICROENVIRONMENT
CARCINOMA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41416-020-0985-5Licence: CC BY

Craig_et_al_BJC_ImmuneStatusIs_AAMAccepted author manuscript, 1.31 MBLicence: Unspecified
Craig_et_alBJC_ImmuneStatusIsPrognosic_VoR
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
Final published version, 1.84 MBLicence: CC BY

Cite this

Craig, S. G., Humphries, M. P., Alderdice, M., Bingham, V., Richman, S. D., Loughrey, M. B., Coleman, H. G., Viratham-Pulsawatdi, A., McCombe, K., Murray, G. I., Blake, A., Domingo, E., Robineau, J., Brown, L., Fisher, D., Seymour, M. T., Quirke, P., Bankhead, P., McQuaid, S., ... Salto-Tellez, M. (2020). Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia. British Journal of Cancer, 123, 1280-1288. https://doi.org/10.1038/s41416-020-0985-5

Craig, SG, Humphries, MP, Alderdice, M, Bingham, V, Richman, SD, Loughrey, MB, Coleman, HG, Viratham-Pulsawatdi, A, McCombe, K, Murray, GI, Blake, A, Domingo, E, Robineau, J, Brown, L, Fisher, D, Seymour, MT, Quirke, P, Bankhead, P, McQuaid, S, Lawler, M, McArt, DG, Maughan, TS, James, JA & Salto-Tellez, M 2020, 'Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia', British Journal of Cancer, vol. 123, pp. 1280-1288. https://doi.org/10.1038/s41416-020-0985-5

@article{07396b02ac5f4b1c8ac01352bcc56c40,

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

abstract = "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.",

keywords = "Cancer microenvironment, colorectal cancer, tumour biomarkers, MICROENVIRONMENT, CARCINOMA",

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

note = "Acknowledgements: PQ is a National Institute of Health Research Senior Investigator. Funding: 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.",

year = "2020",

month = oct,

day = "13",

doi = "10.1038/s41416-020-0985-5",

language = "English",

volume = "123",

pages = "1280--1288",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia

AU - Craig, Stephanie G.

AU - Humphries, Matthew P

AU - Alderdice, Matthew

AU - Bingham, Victoria

AU - Richman, Susan D.

AU - Loughrey, Maurice B.

AU - Coleman, Helen G

AU - Viratham-Pulsawatdi, Amelie

AU - McCombe, Kris

AU - Murray, Graeme I.

AU - Blake, Andrew

AU - Domingo, Enric

AU - Robineau, James

AU - Brown, Louise

AU - Fisher, David

AU - Seymour, Matthew T.

AU - Quirke, Phil

AU - Bankhead, Peter

AU - McQuaid, Stephen

AU - Lawler, Mark

AU - McArt, Darragh G.

AU - Maughan, Tim S.

AU - James, Jacqueline A

AU - Salto-Tellez, Manuel

N1 - Acknowledgements: PQ is a National Institute of Health Research Senior Investigator. Funding: 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.

PY - 2020/10/13

Y1 - 2020/10/13

N2 - 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.

AB - 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.

KW - Cancer microenvironment

KW - colorectal cancer

KW - tumour biomarkers

KW - MICROENVIRONMENT

KW - CARCINOMA

UR - http://www.scopus.com/inward/record.url?scp=85088133186&partnerID=8YFLogxK

U2 - 10.1038/s41416-020-0985-5

DO - 10.1038/s41416-020-0985-5

M3 - Article

C2 - 32684627

VL - 123

SP - 1280

EP - 1288

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this