Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma
Abstract Background The immunogenomic changes triggered by concurrent chemoradiation therapy (CCRT), a standard neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), are unknown. We aimed to analyze the early immunogenomic changes in ESCC induced by CCRT and to correl...
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doaj-cb2b693cf74441ad946e7f9a4bfc069a2020-11-25T02:07:01ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-05-017111410.1186/s40425-019-0609-xPaired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinomaSehhoon Park0Je-Gun Joung1Yang Won Min2Jae-Yong Nam3Daeun Ryu4Dongryul Oh5Woong-Yang Park6Se-Hoon Lee7Yoon La Choi8Jin Seok Ahn9Myung-Ju Ahn10Keunchil Park11Jong-Mu Sun12Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSamsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of MedicineDivision of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSamsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of MedicineSamsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of MedicineDepartment of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of MedicineSamsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of MedicineDivision of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineDepartment of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of MedicineDivision of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineDivision of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineDivision of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineDivision of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineAbstract Background The immunogenomic changes triggered by concurrent chemoradiation therapy (CCRT), a standard neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), are unknown. We aimed to analyze the early immunogenomic changes in ESCC induced by CCRT and to correlate them with clinical outcomes. Methods We collected biopsy samples from 40 patients with ESCC and the surgical candidates were treated with 5-fluorouracil (5-FU)/Cisplatin and concurrent radiation therapy. Endoscopic biopsy was performed before and after one treatment cycle of 5-FU/Cisplatin and 5 to 18 fractions of radiation. We analyzed immunogenomic changes using paired whole-exome sequencing (n = 29) and paired whole-transcriptome sequencing (WTS, n = 23). Multiplex immunohistochemistry (IHC) was conducted in four representative pair samples. Results Fourteen out of 23 WTS samples (60.8%) showed increased immune scores after CCRT, as calculated by ESTIMATE. The rate of progression-free survival was higher in patients with increased immune scores compared with the remaining patients (83.1% vs. 57.1%, p = 0.25). Tumor mutation burden and neoantigen load were significantly reduced after CCRT (p < 0.001). We observed no specific correlation with non-synonymous mutations and no changes in the single-nucleotide variant spectrum after CCRT. Post-CCRT samples were enriched in gene sets related to immune signaling pathways, such as interferon gamma signaling and CD28 co-stimulation. Multiplex IHC showed an incremental trend in the proportion of CD4 positive cells in cytokeratin positive region after CCRT. However, CD8, CD20, FOXP1, PD-L1 showed no definitive trend. Proportion of immune cells calculated by CIBERSORT, showed that significant increase in neutrophils after CCRT. Conclusions We have comprehensively analyzed the early immunogenomic changes induced in ESCC by CCRT and correlated them with clinical outcomes. Our results provide a potential basis for combining immunotherapy with CCRT for the treatment of ESCC.http://link.springer.com/article/10.1186/s40425-019-0609-xEsophageal neoplasmsChemoradiotherapyImmune checkpoint inhibitor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sehhoon Park Je-Gun Joung Yang Won Min Jae-Yong Nam Daeun Ryu Dongryul Oh Woong-Yang Park Se-Hoon Lee Yoon La Choi Jin Seok Ahn Myung-Ju Ahn Keunchil Park Jong-Mu Sun |
spellingShingle |
Sehhoon Park Je-Gun Joung Yang Won Min Jae-Yong Nam Daeun Ryu Dongryul Oh Woong-Yang Park Se-Hoon Lee Yoon La Choi Jin Seok Ahn Myung-Ju Ahn Keunchil Park Jong-Mu Sun Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma Journal for ImmunoTherapy of Cancer Esophageal neoplasms Chemoradiotherapy Immune checkpoint inhibitor |
author_facet |
Sehhoon Park Je-Gun Joung Yang Won Min Jae-Yong Nam Daeun Ryu Dongryul Oh Woong-Yang Park Se-Hoon Lee Yoon La Choi Jin Seok Ahn Myung-Ju Ahn Keunchil Park Jong-Mu Sun |
author_sort |
Sehhoon Park |
title |
Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma |
title_short |
Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma |
title_full |
Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma |
title_fullStr |
Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma |
title_full_unstemmed |
Paired whole exome and transcriptome analyses for the Immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma |
title_sort |
paired whole exome and transcriptome analyses for the immunogenomic changes during concurrent chemoradiotherapy in esophageal squamous cell carcinoma |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2019-05-01 |
description |
Abstract Background The immunogenomic changes triggered by concurrent chemoradiation therapy (CCRT), a standard neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), are unknown. We aimed to analyze the early immunogenomic changes in ESCC induced by CCRT and to correlate them with clinical outcomes. Methods We collected biopsy samples from 40 patients with ESCC and the surgical candidates were treated with 5-fluorouracil (5-FU)/Cisplatin and concurrent radiation therapy. Endoscopic biopsy was performed before and after one treatment cycle of 5-FU/Cisplatin and 5 to 18 fractions of radiation. We analyzed immunogenomic changes using paired whole-exome sequencing (n = 29) and paired whole-transcriptome sequencing (WTS, n = 23). Multiplex immunohistochemistry (IHC) was conducted in four representative pair samples. Results Fourteen out of 23 WTS samples (60.8%) showed increased immune scores after CCRT, as calculated by ESTIMATE. The rate of progression-free survival was higher in patients with increased immune scores compared with the remaining patients (83.1% vs. 57.1%, p = 0.25). Tumor mutation burden and neoantigen load were significantly reduced after CCRT (p < 0.001). We observed no specific correlation with non-synonymous mutations and no changes in the single-nucleotide variant spectrum after CCRT. Post-CCRT samples were enriched in gene sets related to immune signaling pathways, such as interferon gamma signaling and CD28 co-stimulation. Multiplex IHC showed an incremental trend in the proportion of CD4 positive cells in cytokeratin positive region after CCRT. However, CD8, CD20, FOXP1, PD-L1 showed no definitive trend. Proportion of immune cells calculated by CIBERSORT, showed that significant increase in neutrophils after CCRT. Conclusions We have comprehensively analyzed the early immunogenomic changes induced in ESCC by CCRT and correlated them with clinical outcomes. Our results provide a potential basis for combining immunotherapy with CCRT for the treatment of ESCC. |
topic |
Esophageal neoplasms Chemoradiotherapy Immune checkpoint inhibitor |
url |
http://link.springer.com/article/10.1186/s40425-019-0609-x |
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