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

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

doi: 10.1097/SLA.0000000000002410

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.

*Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD

Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, United States

Department of Pathology and Laboratory Medicine, Allegheny Health Network, Pittsburgh, PA

§Division of Radiation Oncology, Allegheny Health Network, Pittsburgh, PA

Esophageal Diseases Center, VA North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, TX.

Reprints: Blair A. Jobe, MD, Esophageal and Lung Institute, Allegheny Health Network, 4600 North Tower, 4800 Friendship Avenue, Pittsburgh, PA 15224. E-mail:

Grant Support: David E. Gold & Irene Blumenkranz, Cole Foundation and GI SPORE CDA to RJK (NIH grant CA62924). SKCCC core grant NCI CCSG P30 CA006973.

Gene G. Finley, MD provided support by advising on clinical context. Michael Berman, MD and Mahpareh Mostoufi, MD provided support for pathology slide review. Emily Lloyd, BS provided regulatory support. Olivier Gayou, provided support in determining the radiation dose for animal studies.

The authors report no conflicts of interest.

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