Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an ‘Immune Cold’ Phenotype Associated with Poor Survival

Ross J. Porter; Graeme I. Murray; Sandra Hapca; Andrew Hay; Stephanie G. Craig; Matthew P. Humphries; Jacqueline A. James; Manuel Salto-Tellez; Daniel P. Brice; Susan H. Berry; Mairi H. McLean

doi:10.3390/cancers15061865

Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an ‘Immune Cold’ Phenotype Associated with Poor Survival

Ross J. Porter, Graeme I. Murray, Sandra Hapca, Andrew Hay, Stephanie G. Craig, Matthew P. Humphries, Jacqueline A. James, Manuel Salto-Tellez, Daniel P. Brice, Susan H. Berry, Mairi H. McLean^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an ‘immune cold’ tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC.

Original language	English
Article number	1865
Number of pages	16
Journal	Cancers
Volume	15
Issue number	6
Early online date	20 Mar 2023
DOIs	https://doi.org/10.3390/cancers15061865
Publication status	Published - 20 Mar 2023

Bibliographical note

Acknowledgments: The authors would like to thank NHS Grampian Biorepository, in particular Joan Wilson, Victoria Morrison, Kristine Nellany, and Nadine Hay, for their assistance in preparing tissue for this project. The authors also thank Tasneem O Atezia and Christina A Christopoulou for their contribution to this project during their time in the McLean laboratory. The laboratory work was instigated when M.H.M., R.J.P. and D.P.B. were based at the Institute of Medical Sciences, University
of Aberdeen.
Funding
This work was funded by project grants from NHS Grampian Endowments and Friends of Anchor (https://www.friendsofanchor.org, charity no. SC025332). Within the McLean laboratory at the University of Aberdeen, SH received a Medical Research Scotland Summer Studentship, and AH received an Aberdeen Summer Research Studentship (University of Aberdeen).

Keywords

HMGB1
colorectal cancer
mismatch repair
lymphocytes
cytokine
therapy

UN SDGs

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

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10.3390/cancers15061865Licence: CC BY

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Porter, R. J., Murray, G. I., Hapca, S., Hay, A., Craig, S. G., Humphries, M. P., James, J. A., Salto-Tellez, M., Brice, D. P., Berry, S. H., & McLean, M. H. (2023). Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an ‘Immune Cold’ Phenotype Associated with Poor Survival. Cancers, 15(6), Article 1865. https://doi.org/10.3390/cancers15061865

Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an ‘Immune Cold’ Phenotype Associated with Poor Survival. / Porter, Ross J.; Murray, Graeme I.; Hapca, Sandra et al.
In: Cancers, Vol. 15, No. 6, 1865, 20.03.2023.

Research output: Contribution to journal › Article › peer-review

Porter, RJ, Murray, GI, Hapca, S, Hay, A, Craig, SG, Humphries, MP, James, JA, Salto-Tellez, M, Brice, DP, Berry, SH & McLean, MH 2023, 'Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an ‘Immune Cold’ Phenotype Associated with Poor Survival', Cancers, vol. 15, no. 6, 1865. https://doi.org/10.3390/cancers15061865

Porter RJ, Murray GI, Hapca S, Hay A, Craig SG, Humphries MP et al. Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an ‘Immune Cold’ Phenotype Associated with Poor Survival. Cancers. 2023 Mar 20;15(6):1865. Epub 2023 Mar 20. doi: 10.3390/cancers15061865

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title = "Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an {\textquoteleft}Immune Cold{\textquoteright} Phenotype Associated with Poor Survival",

abstract = "New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an {\textquoteleft}immune cold{\textquoteright} tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC.",

keywords = "HMGB1, colorectal cancer, mismatch repair, lymphocytes, cytokine, therapy",

author = "Porter, {Ross J.} and Murray, {Graeme I.} and Sandra Hapca and Andrew Hay and Craig, {Stephanie G.} and Humphries, {Matthew P.} and James, {Jacqueline A.} and Manuel Salto-Tellez and Brice, {Daniel P.} and Berry, {Susan H.} and McLean, {Mairi H.}",

note = "Acknowledgments: The authors would like to thank NHS Grampian Biorepository, in particular Joan Wilson, Victoria Morrison, Kristine Nellany, and Nadine Hay, for their assistance in preparing tissue for this project. The authors also thank Tasneem O Atezia and Christina A Christopoulou for their contribution to this project during their time in the McLean laboratory. The laboratory work was instigated when M.H.M., R.J.P. and D.P.B. were based at the Institute of Medical Sciences, University of Aberdeen. Funding This work was funded by project grants from NHS Grampian Endowments and Friends of Anchor (https://www.friendsofanchor.org, charity no. SC025332). Within the McLean laboratory at the University of Aberdeen, SH received a Medical Research Scotland Summer Studentship, and AH received an Aberdeen Summer Research Studentship (University of Aberdeen).",

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AU - Porter, Ross J.

AU - Murray, Graeme I.

AU - Hapca, Sandra

AU - Hay, Andrew

AU - Craig, Stephanie G.

AU - Humphries, Matthew P.

AU - James, Jacqueline A.

AU - Salto-Tellez, Manuel

AU - Brice, Daniel P.

AU - Berry, Susan H.

AU - McLean, Mairi H.

N1 - Acknowledgments: The authors would like to thank NHS Grampian Biorepository, in particular Joan Wilson, Victoria Morrison, Kristine Nellany, and Nadine Hay, for their assistance in preparing tissue for this project. The authors also thank Tasneem O Atezia and Christina A Christopoulou for their contribution to this project during their time in the McLean laboratory. The laboratory work was instigated when M.H.M., R.J.P. and D.P.B. were based at the Institute of Medical Sciences, University of Aberdeen. Funding This work was funded by project grants from NHS Grampian Endowments and Friends of Anchor (https://www.friendsofanchor.org, charity no. SC025332). Within the McLean laboratory at the University of Aberdeen, SH received a Medical Research Scotland Summer Studentship, and AH received an Aberdeen Summer Research Studentship (University of Aberdeen).

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N2 - New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an ‘immune cold’ tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC.

AB - New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an ‘immune cold’ tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC.

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KW - colorectal cancer

KW - mismatch repair

KW - lymphocytes

KW - cytokine

KW - therapy

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