The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

Matthew P. Humphries; Stephanie G. Craig; Rafal Kacprzyk; Natalie C. Fisher; Victoria Bingham; Stephen McQuaid; Graeme I. Murray; Damian McManus; Richard C. Turkington; Jacqueline James; Manuel Salto-Tellez

doi:10.1186/s12885-020-06987-y

The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

Matthew P. Humphries, Stephanie G. Craig, Rafal Kacprzyk, Natalie C. Fisher, Victoria Bingham, Stephen McQuaid, Graeme I. Murray, Damian McManus, Richard C. Turkington, Jacqueline James, Manuel Salto-Tellez^* (Corresponding Author)

^*Corresponding author for this work

Applied Medicine

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Abstract

Background Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. Methods Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density. Results CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223–0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363–0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS. Conclusions Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.

Original language	English
Article number	500
Number of pages	11
Journal	BMC Cancer
Volume	20
DOIs	https://doi.org/10.1186/s12885-020-06987-y
Publication status	Published - 1 Jun 2020

Bibliographical note

Acknowledgments
The samples used in this research were received from the Northern Ireland Biobank, which has ethical approval to use de-identified tissue samples from the Belfast Health and Social Care Tissue Pathology archive (REC:11/NI/0013). The Northern Ireland Molecular Pathology Laboratory, was responsible for construction of tissue microarrays, slide staining, and scanning. We are grateful to the NVIDIA Corporation for supporting our research via the GPU Grant Program for researchers. The research leading to these results has also received funding from Invest Northern Ireland. The authors thank Mr. Ken Arthur for the construction of the original tissue microarrays used in this study.

Funding
This study was funded by a CRUK Accelerator Grant (A20256) to JJ and MST. CRUK had no role in the study design, collection, analysis, and interpretation of the data or in the writing of the report.

Keywords

Esophageal adenocarcinoma
Immune checkpoint
Multiplex IHC
Image analysis
BIOMARKERS
SURVIVAL
PROGRAMMED DEATH-1
PROGNOSTIC-SIGNIFICANCE
LARGE COHORT
CANCER
LIGAND 1 EXPRESSION

UN SDGs

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

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Cite this

Humphries, M. P., Craig, S. G., Kacprzyk, R., Fisher, N. C., Bingham, V., McQuaid, S., Murray, G. I., McManus, D., Turkington, R. C., James, J., & Salto-Tellez, M. (2020). The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation. BMC Cancer, 20, Article 500. https://doi.org/10.1186/s12885-020-06987-y

@article{52c8c03989124066b667100b1ebee248,

title = "The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation",

abstract = "Background Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. Methods Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density. Results CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223–0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363–0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS. Conclusions Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.",

keywords = "Esophageal adenocarcinoma, Immune checkpoint, Multiplex IHC, Image analysis, BIOMARKERS, SURVIVAL, PROGRAMMED DEATH-1, PROGNOSTIC-SIGNIFICANCE, LARGE COHORT, CANCER, LIGAND 1 EXPRESSION",

author = "Humphries, {Matthew P.} and Craig, {Stephanie G.} and Rafal Kacprzyk and Fisher, {Natalie C.} and Victoria Bingham and Stephen McQuaid and Murray, {Graeme I.} and Damian McManus and Turkington, {Richard C.} and Jacqueline James and Manuel Salto-Tellez",

note = "Acknowledgments The samples used in this research were received from the Northern Ireland Biobank, which has ethical approval to use de-identified tissue samples from the Belfast Health and Social Care Tissue Pathology archive (REC:11/NI/0013). The Northern Ireland Molecular Pathology Laboratory, was responsible for construction of tissue microarrays, slide staining, and scanning. We are grateful to the NVIDIA Corporation for supporting our research via the GPU Grant Program for researchers. The research leading to these results has also received funding from Invest Northern Ireland. The authors thank Mr. Ken Arthur for the construction of the original tissue microarrays used in this study. Funding This study was funded by a CRUK Accelerator Grant (A20256) to JJ and MST. CRUK had no role in the study design, collection, analysis, and interpretation of the data or in the writing of the report.",

year = "2020",

month = jun,

day = "1",

doi = "10.1186/s12885-020-06987-y",

language = "English",

volume = "20",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "BioMed Central",

}

TY - JOUR

T1 - The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

AU - Humphries, Matthew P.

AU - Craig, Stephanie G.

AU - Kacprzyk, Rafal

AU - Fisher, Natalie C.

AU - Bingham, Victoria

AU - McQuaid, Stephen

AU - Murray, Graeme I.

AU - McManus, Damian

AU - Turkington, Richard C.

AU - James, Jacqueline

AU - Salto-Tellez, Manuel

N1 - Acknowledgments The samples used in this research were received from the Northern Ireland Biobank, which has ethical approval to use de-identified tissue samples from the Belfast Health and Social Care Tissue Pathology archive (REC:11/NI/0013). The Northern Ireland Molecular Pathology Laboratory, was responsible for construction of tissue microarrays, slide staining, and scanning. We are grateful to the NVIDIA Corporation for supporting our research via the GPU Grant Program for researchers. The research leading to these results has also received funding from Invest Northern Ireland. The authors thank Mr. Ken Arthur for the construction of the original tissue microarrays used in this study. Funding This study was funded by a CRUK Accelerator Grant (A20256) to JJ and MST. CRUK had no role in the study design, collection, analysis, and interpretation of the data or in the writing of the report.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - Background Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. Methods Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density. Results CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223–0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363–0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS. Conclusions Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.

AB - Background Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. Methods Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density. Results CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223–0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363–0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS. Conclusions Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.

KW - Esophageal adenocarcinoma

KW - Immune checkpoint

KW - Multiplex IHC

KW - Image analysis

KW - BIOMARKERS

KW - SURVIVAL

KW - PROGRAMMED DEATH-1

KW - PROGNOSTIC-SIGNIFICANCE

KW - LARGE COHORT

KW - CANCER

KW - LIGAND 1 EXPRESSION

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U2 - 10.1186/s12885-020-06987-y

DO - 10.1186/s12885-020-06987-y

M3 - Article

C2 - 32487090

SN - 1471-2407

VL - 20

JO - BMC Cancer

JF - BMC Cancer

M1 - 500

ER -

The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

Abstract

Bibliographical note

Keywords

UN SDGs

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