Natural killer-like signature observed post therapy in locally advanced rectal cancer is a determinant of pathological response and improved survival

Matthew Alderdice, Philip D. Dunne, Aidan J Cole, Paul G. O'Reilly, Darragh G. McArt, Vicky Bingham, Marc-Aurel Fuchs, Stephen McQuaid, Maurice B. Loughrey, Graeme I Murray, Leslie Samuel, Mark Lawler, Richard H. Wilson, Manuel Salto-Tellez (Corresponding Author), Vicky M. Coyle (Corresponding Author)

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Abstract

Around 12–15% of patients with locally advanced rectal cancer undergo a pathologically complete response (tumor regression grade 4) to long-course preoperative chemoradiotherapy; the remainder exhibit a spectrum of tumor regression (tumor regression grade 1–3). Understanding therapy-related transcriptional alterations may enable better prediction of response as measured by progression-free and overall survival, in addition to aiding the development of improved strategies based on the underlying biology of the disease. To this end, we performed high-throughput gene expression profiling in 40 pairs of formalin-fixed paraffin-embedded rectal cancer biopsies and matched resections following long-course preoperative chemoradiotherapy (discovery cohort). Differential gene expression analysis was performed contrasting tumor regression grades in resections. Enumeration of the tumor microenvironment cell population was undertaken using in silico analysis of the transcriptional data, and real-time PCR validation of NCR1 undertaken. Immunohistochemistry and survival analysis was used to measure CD56+ cell populations in an independent cohort (n=150). Gene expression traits observed following long-course preoperative chemoradiotherapy in the discovery cohort suggested an increased abundance of natural killer cells in tumors that displayed a clinical response to CRT in a tumor regression grade-dependent manner. CD56+ natural killer-cell populations were measured by immunohistochemistry and found to be significantly higher in tumor regression grade 3 patients compared with tumor regression grade 1–2 in the validation cohort. Furthermore, it was observed that patients positive for CD56 cells after therapy had a better overall survival (HR=0.282, 95% CI=0.109–0.729, χ2=7.854, P=0.005). In conclusion, we have identified a novel post-therapeutic natural killer-like transcription signature in patients responding to long-course preoperative chemoradiotherapy. Furthermore, patients with a higher abundance of CD56-positive natural killer cells post long-course preoperative chemoradiotherapy had better overall survival. Therefore, harnessing a natural killer-like response after therapy may improve outcomes for locally advanced rectal cancer patients. Finally, we hypothesize that future assessment of this natural killer-like response in on-treatment biopsy material may inform clinical decision-making for treatment duration.
Original languageEnglish
Pages (from-to)1287-1298
Number of pages12
JournalModern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Volume30
Issue number9
Early online date16 Jun 2017
DOIs
Publication statusPublished - Sep 2017

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Rectal Neoplasms
Chemoradiotherapy
Survival
Neoplasms
Natural Killer Cells
Therapeutics
Immunohistochemistry
Population
Biopsy
Gene Expression
Tumor Microenvironment
Gene Expression Profiling
Survival Analysis
Cell- and Tissue-Based Therapy
Computer Simulation
Paraffin
Formaldehyde
Disease-Free Survival
Real-Time Polymerase Chain Reaction

Keywords

  • natural killer cells
  • rectal cancer
  • tumour regression
  • gene expression
  • chemoradiotherapy

Cite this

Natural killer-like signature observed post therapy in locally advanced rectal cancer is a determinant of pathological response and improved survival. / Alderdice, Matthew ; Dunne, Philip D. ; Cole, Aidan J ; O'Reilly, Paul G. ; McArt, Darragh G.; Bingham, Vicky ; Fuchs, Marc-Aurel; McQuaid, Stephen; Loughrey, Maurice B. ; Murray, Graeme I; Samuel, Leslie; Lawler, Mark; Wilson, Richard H. ; Salto-Tellez, Manuel (Corresponding Author); Coyle, Vicky M. (Corresponding Author).

In: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Vol. 30, No. 9, 09.2017, p. 1287-1298.

Research output: Contribution to journalArticle

Alderdice, Matthew ; Dunne, Philip D. ; Cole, Aidan J ; O'Reilly, Paul G. ; McArt, Darragh G. ; Bingham, Vicky ; Fuchs, Marc-Aurel ; McQuaid, Stephen ; Loughrey, Maurice B. ; Murray, Graeme I ; Samuel, Leslie ; Lawler, Mark ; Wilson, Richard H. ; Salto-Tellez, Manuel ; Coyle, Vicky M. . / Natural killer-like signature observed post therapy in locally advanced rectal cancer is a determinant of pathological response and improved survival. In: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2017 ; Vol. 30, No. 9. pp. 1287-1298.
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abstract = "Around 12–15{\%} of patients with locally advanced rectal cancer undergo a pathologically complete response (tumor regression grade 4) to long-course preoperative chemoradiotherapy; the remainder exhibit a spectrum of tumor regression (tumor regression grade 1–3). Understanding therapy-related transcriptional alterations may enable better prediction of response as measured by progression-free and overall survival, in addition to aiding the development of improved strategies based on the underlying biology of the disease. To this end, we performed high-throughput gene expression profiling in 40 pairs of formalin-fixed paraffin-embedded rectal cancer biopsies and matched resections following long-course preoperative chemoradiotherapy (discovery cohort). Differential gene expression analysis was performed contrasting tumor regression grades in resections. Enumeration of the tumor microenvironment cell population was undertaken using in silico analysis of the transcriptional data, and real-time PCR validation of NCR1 undertaken. Immunohistochemistry and survival analysis was used to measure CD56+ cell populations in an independent cohort (n=150). Gene expression traits observed following long-course preoperative chemoradiotherapy in the discovery cohort suggested an increased abundance of natural killer cells in tumors that displayed a clinical response to CRT in a tumor regression grade-dependent manner. CD56+ natural killer-cell populations were measured by immunohistochemistry and found to be significantly higher in tumor regression grade 3 patients compared with tumor regression grade 1–2 in the validation cohort. Furthermore, it was observed that patients positive for CD56 cells after therapy had a better overall survival (HR=0.282, 95{\%} CI=0.109–0.729, χ2=7.854, P=0.005). In conclusion, we have identified a novel post-therapeutic natural killer-like transcription signature in patients responding to long-course preoperative chemoradiotherapy. Furthermore, patients with a higher abundance of CD56-positive natural killer cells post long-course preoperative chemoradiotherapy had better overall survival. Therefore, harnessing a natural killer-like response after therapy may improve outcomes for locally advanced rectal cancer patients. Finally, we hypothesize that future assessment of this natural killer-like response in on-treatment biopsy material may inform clinical decision-making for treatment duration.",
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T1 - Natural killer-like signature observed post therapy in locally advanced rectal cancer is a determinant of pathological response and improved survival

AU - Alderdice, Matthew

AU - Dunne, Philip D.

AU - Cole, Aidan J

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AU - McArt, Darragh G.

AU - Bingham, Vicky

AU - Fuchs, Marc-Aurel

AU - McQuaid, Stephen

AU - Loughrey, Maurice B.

AU - Murray, Graeme I

AU - Samuel, Leslie

AU - Lawler, Mark

AU - Wilson, Richard H.

AU - Salto-Tellez, Manuel

AU - Coyle, Vicky M.

N1 - This work was supported by a very generous grant from the Sean Crummey Memorial Fund. The staff and infrastructure provided by the N. Ireland Biobank and the Belfast Experimental Cancer Medicine Centre allowed this research to take place. These are supported by the Research and Development Division of the N. Ireland Public Health Agency and Cancer Research UK. We would also like to express our gratitude to the staff at the Grampian Biorepository for providing the Tissue microarray materials for validation purposes.

PY - 2017/9

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N2 - Around 12–15% of patients with locally advanced rectal cancer undergo a pathologically complete response (tumor regression grade 4) to long-course preoperative chemoradiotherapy; the remainder exhibit a spectrum of tumor regression (tumor regression grade 1–3). Understanding therapy-related transcriptional alterations may enable better prediction of response as measured by progression-free and overall survival, in addition to aiding the development of improved strategies based on the underlying biology of the disease. To this end, we performed high-throughput gene expression profiling in 40 pairs of formalin-fixed paraffin-embedded rectal cancer biopsies and matched resections following long-course preoperative chemoradiotherapy (discovery cohort). Differential gene expression analysis was performed contrasting tumor regression grades in resections. Enumeration of the tumor microenvironment cell population was undertaken using in silico analysis of the transcriptional data, and real-time PCR validation of NCR1 undertaken. Immunohistochemistry and survival analysis was used to measure CD56+ cell populations in an independent cohort (n=150). Gene expression traits observed following long-course preoperative chemoradiotherapy in the discovery cohort suggested an increased abundance of natural killer cells in tumors that displayed a clinical response to CRT in a tumor regression grade-dependent manner. CD56+ natural killer-cell populations were measured by immunohistochemistry and found to be significantly higher in tumor regression grade 3 patients compared with tumor regression grade 1–2 in the validation cohort. Furthermore, it was observed that patients positive for CD56 cells after therapy had a better overall survival (HR=0.282, 95% CI=0.109–0.729, χ2=7.854, P=0.005). In conclusion, we have identified a novel post-therapeutic natural killer-like transcription signature in patients responding to long-course preoperative chemoradiotherapy. Furthermore, patients with a higher abundance of CD56-positive natural killer cells post long-course preoperative chemoradiotherapy had better overall survival. Therefore, harnessing a natural killer-like response after therapy may improve outcomes for locally advanced rectal cancer patients. Finally, we hypothesize that future assessment of this natural killer-like response in on-treatment biopsy material may inform clinical decision-making for treatment duration.

AB - Around 12–15% of patients with locally advanced rectal cancer undergo a pathologically complete response (tumor regression grade 4) to long-course preoperative chemoradiotherapy; the remainder exhibit a spectrum of tumor regression (tumor regression grade 1–3). Understanding therapy-related transcriptional alterations may enable better prediction of response as measured by progression-free and overall survival, in addition to aiding the development of improved strategies based on the underlying biology of the disease. To this end, we performed high-throughput gene expression profiling in 40 pairs of formalin-fixed paraffin-embedded rectal cancer biopsies and matched resections following long-course preoperative chemoradiotherapy (discovery cohort). Differential gene expression analysis was performed contrasting tumor regression grades in resections. Enumeration of the tumor microenvironment cell population was undertaken using in silico analysis of the transcriptional data, and real-time PCR validation of NCR1 undertaken. Immunohistochemistry and survival analysis was used to measure CD56+ cell populations in an independent cohort (n=150). Gene expression traits observed following long-course preoperative chemoradiotherapy in the discovery cohort suggested an increased abundance of natural killer cells in tumors that displayed a clinical response to CRT in a tumor regression grade-dependent manner. CD56+ natural killer-cell populations were measured by immunohistochemistry and found to be significantly higher in tumor regression grade 3 patients compared with tumor regression grade 1–2 in the validation cohort. Furthermore, it was observed that patients positive for CD56 cells after therapy had a better overall survival (HR=0.282, 95% CI=0.109–0.729, χ2=7.854, P=0.005). In conclusion, we have identified a novel post-therapeutic natural killer-like transcription signature in patients responding to long-course preoperative chemoradiotherapy. Furthermore, patients with a higher abundance of CD56-positive natural killer cells post long-course preoperative chemoradiotherapy had better overall survival. Therefore, harnessing a natural killer-like response after therapy may improve outcomes for locally advanced rectal cancer patients. Finally, we hypothesize that future assessment of this natural killer-like response in on-treatment biopsy material may inform clinical decision-making for treatment duration.

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KW - rectal cancer

KW - tumour regression

KW - gene expression

KW - chemoradiotherapy

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M3 - Article

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JO - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

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