Understanding immune phenotypes in human gastric disease tissues by multiplexed immunohistochemistry

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Abstract

Background

Understanding immune phenotypes and human gastric disease in situ requires an approach that leverages multiplexed immunohistochemistry (mIHC) with multispectral imaging to facilitate precise image analyses.

Methods

We developed a novel 4-color mIHC assay based on tyramide signal amplification that allowed us to reliably interrogate immunologic checkpoints, including programmed death-ligand 1 (PD-L1), cytotoxic T cells (CD8 ⁺T) and regulatory T cells (Foxp3), in formalin-fixed, paraffin-embedded tissues of various human gastric diseases. By observing cell phenotypes within the disease tissue microenvironment, we were able to determine specific co-localized staining combinations and various measures of cell density.

Results

We found that PD-L1 was expressed in gastric ulcer and in tumor cells (TCs), as well as in tumor-infiltrating immune cells (TIICs), but not in normal gastric mucosa or other gastric intraepithelial neoplastic tissues. Furthermore, we found no significant reduction in CD8 ⁺T cells, whereas the ratio of CD8 ⁺T:Foxp3 cells and CD8 ⁺T:PD-L1 cells was suppressed in tumor tissues and elevated in adjacent normal tissues. An unsupervised hierarchical analysis also identified correlations between CD8 ⁺T and Foxp3 ⁺ tumor-infiltrating lymphocyte (TIL) densities and average PD-L1 levels. Three main groups were identified based on the results of CD8 ⁺T:PD-L1 ratios in gastric tumor tissues. Furthermore, integrating CD8 ⁺T:Foxp3 ratios, which increased the complexity for immune phenotype status, revealed 6–7 clusters that enabled the separation of gastric cancer patients at the same clinical stage into different risk-group subsets.

Conclusions

Characterizing immune phenotypes in human gastric disease tissues via multiplexed immunohistochemistry may help guide PD-L1 clinical therapy. Observing unique disease tissue microenvironments can improve our understanding of immune phenotypes and cell interactions within these microenvironments, providing the ability to predict safe responses to immunotherapies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12967-017-1311-8) contains supplementary material, which is available to authorized users.

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Most cited references 17

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The blockade of immune checkpoints in cancer immunotherapy.

Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.

Paul Salama, Michael Phillips, Fabienne Grieu … (2009)

To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities. Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.

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Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.

Elizabeth Thompson, Marianna Zahurak, Adrian Murphy … (2017)

Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival.

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Author and article information

Contributors

Le Ying: le.ying@hudson.org.au

Feng Yan: feng.yan@hudson.org.au

Qiaohong Meng: iammqh@163.com

Xiangliang Yuan: yuanxiangliang@gmail.com

Liang Yu: liang.yu@monash.edu

Bryan R. G. Williams: bryan.williams@hudson.org.au

David W. Chan: dwchan@hku.hk

Liyun Shi: shi_liyun@msn.com

Yugang Tu: william.tu@cst-c.com.cn

Peihua Ni: nipeihua@126.com

Xuefeng Wang: wangxuefeng6336@hotmail.com

Dakang Xu: dakang.xu@monash.edu

Yiqun Hu: +86 21 63867812 , ichunhu@126.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 12 October 2017

Publication date PMC-release: 12 October 2017

Publication date Collection: 2017

Volume: 15

Electronic Location Identifier: 206

Affiliations

[1 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, , Shanghai Jiao Tong University, ; 227 Chongqing Road South, Shanghai, 200025 China

[2 ]ISNI 0000 0001 2230 9154, GRID grid.410595.c, Institute of Ageing Research, Hangzhou Normal University School of Medicine, ; Hangzhou, China

[3 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Tea Science, , Zhejiang University, ; Hangzhou, China

[4 ]ISNI 0000 0004 1760 4628, GRID grid.412478.c, Department of General Surgery, , Shanghai Jiao Tong University Affiliated First People’s Hospital, ; Shanghai, China

[5 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Hudson Institute of Medical Research, Department of Molecular and Translational Science, , Monash University, ; Clayton, VIC Australia

[6 ]Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P. R. China

[7 ]ISNI 0000 0004 1765 1045, GRID grid.410745.3, Department of Microbiology and Immunology, , Nanjing University of Chinese Medicine, ; Nanjing, 210046 China

[8 ]GRID grid.420530.0, Cell Signaling Technology, Inc., Asia Pacific, ; Danvers, USA

[9 ]GRID grid.415869.7, Department of Laboratory Medicine, Ruijin Hospital, , Shanghai Jiaotong University School of Medicine, ; Shanghai, China

Article

Publisher ID: 1311

DOI: 10.1186/s12967-017-1311-8

PMC ID: 5639762

PubMed ID: 29025424

SO-VID: a3f8f1a5-7bdb-472e-915e-f78b36f6dda1

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 April 2017

Date accepted : 4 October 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81273247

Award ID: 81472655

Award ID: 31670905

Award Recipient : Dakang Xu

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ScienceOpen disciplines: Medicine

Keywords: human gastric disease,immune phenotypes,multiplexed immunohistochemistry

Data availability:

ScienceOpen disciplines: Medicine

Keywords: human gastric disease, immune phenotypes, multiplexed immunohistochemistry

Understanding immune phenotypes in human gastric disease tissues by multiplexed immunohistochemistry

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

HLA-G and immune tolerance in pregnancy

Most cited references 17

The blockade of immune checkpoints in cancer immunotherapy.

Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.

Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.

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