The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation

Ronan J. Kelly, Ali H. Zaidi, Matthew A. Smith, Ashten N. Omstead, Juliann E. Kosovec, Daisuke Matsui, Samantha A. Martin, Christina DiCarlo, E. Day Werts, Jan F. Silverman, David H Wang, Blair A. Jobe

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients. METHODS: To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation. RESULTS: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure. CONCLUSIONS: Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors.

Original languageEnglish (US)
Pages (from-to)992-999
Number of pages8
JournalAnnals of Surgery
Volume268
Issue number6
DOIs
StatePublished - Dec 1 2018

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Adenocarcinoma
Up-Regulation
Radiation
Neoplasms
Reverse Transcriptase Polymerase Chain Reaction
Tumor-Infiltrating Lymphocytes
Esophageal Neoplasms
Gastroesophageal Reflux
Interferons
Radiotherapy
Animal Models
Immunohistochemistry
Clinical Trials
Ligands
T-Lymphocytes
Biopsy
Safety

ASJC Scopus subject areas

  • Surgery

Cite this

Kelly, R. J., Zaidi, A. H., Smith, M. A., Omstead, A. N., Kosovec, J. E., Matsui, D., ... Jobe, B. A. (2018). The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation. Annals of Surgery, 268(6), 992-999. https://doi.org/10.1097/SLA.0000000000002410

The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation. / Kelly, Ronan J.; Zaidi, Ali H.; Smith, Matthew A.; Omstead, Ashten N.; Kosovec, Juliann E.; Matsui, Daisuke; Martin, Samantha A.; DiCarlo, Christina; Werts, E. Day; Silverman, Jan F.; Wang, David H; Jobe, Blair A.

In: Annals of Surgery, Vol. 268, No. 6, 01.12.2018, p. 992-999.

Research output: Contribution to journalArticle

Kelly, RJ, Zaidi, AH, Smith, MA, Omstead, AN, Kosovec, JE, Matsui, D, Martin, SA, DiCarlo, C, Werts, ED, Silverman, JF, Wang, DH & Jobe, BA 2018, 'The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation', Annals of Surgery, vol. 268, no. 6, pp. 992-999. https://doi.org/10.1097/SLA.0000000000002410
Kelly, Ronan J. ; Zaidi, Ali H. ; Smith, Matthew A. ; Omstead, Ashten N. ; Kosovec, Juliann E. ; Matsui, Daisuke ; Martin, Samantha A. ; DiCarlo, Christina ; Werts, E. Day ; Silverman, Jan F. ; Wang, David H ; Jobe, Blair A. / The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation. In: Annals of Surgery. 2018 ; Vol. 268, No. 6. pp. 992-999.
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AU - Omstead, Ashten N.

AU - Kosovec, Juliann E.

AU - Matsui, Daisuke

AU - Martin, Samantha A.

AU - DiCarlo, Christina

AU - Werts, E. Day

AU - Silverman, Jan F.

AU - Wang, David H

AU - Jobe, Blair A.

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AB - OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients. METHODS: To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation. RESULTS: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure. CONCLUSIONS: Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors.

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