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

Publication ,  Journal Article
Kelly, RJ; Zaidi, AH; Smith, MA; Omstead, AN; Kosovec, JE; Matsui, D; Martin, SA; DiCarlo, C; Werts, ED; Silverman, JF; Wang, DH; Jobe, BA
Published in: Annals of surgery
December 2018

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.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.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.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.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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Published In

Annals of surgery

DOI

EISSN

1528-1140

ISSN

0003-4932

Publication Date

December 2018

Volume

268

Issue

6

Start / End Page

992 / 999

Related Subject Headings

  • Up-Regulation
  • Tumor Microenvironment
  • Surgery
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats
  • Middle Aged
  • Male
  • Lymphocytes, Tumor-Infiltrating
  • Immunohistochemistry
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
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
Kelly, Ronan J., Ali H. Zaidi, Matthew A. Smith, Ashten N. Omstead, Juliann E. Kosovec, Daisuke Matsui, Samantha A. Martin, et al. “The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation.Annals of Surgery 268, no. 6 (December 2018): 992–99. https://doi.org/10.1097/sla.0000000000002410.
Kelly RJ, Zaidi AH, Smith MA, Omstead AN, Kosovec JE, Matsui D, et al. The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation. Annals of surgery. 2018 Dec;268(6):992–9.
Kelly, Ronan J., et al. “The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation.Annals of Surgery, vol. 268, no. 6, Dec. 2018, pp. 992–99. Epmc, doi:10.1097/sla.0000000000002410.
Kelly RJ, Zaidi AH, Smith MA, Omstead AN, Kosovec JE, Matsui D, Martin SA, DiCarlo C, Werts ED, Silverman JF, Wang DH, Jobe BA. The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation. Annals of surgery. 2018 Dec;268(6):992–999.

Published In

Annals of surgery

DOI

EISSN

1528-1140

ISSN

0003-4932

Publication Date

December 2018

Volume

268

Issue

6

Start / End Page

992 / 999

Related Subject Headings

  • Up-Regulation
  • Tumor Microenvironment
  • Surgery
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats
  • Middle Aged
  • Male
  • Lymphocytes, Tumor-Infiltrating
  • Immunohistochemistry
  • Humans