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Open Access 01-02-2025 | Esophageal Cancer | Research

Prognostic immune markers in esophageal cancer patients managed with trimodal therapy

Authors: Mark K. Farrugia, Elizabeth A. Repasky, Minhui Chen, Kristopher Attwood, Kayla Catalfamo, Hanna Rosenheck, Song Yao, David M. Mattson, Sarbajit Mukherjee, Moshim Kukar, Agnieszka K. Witkiewicz, Anurag K. Singh

Published in: Cancer Immunology, Immunotherapy | Issue 2/2025

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Abstract

Background

Esophageal cancer (ESC) is an aggressive disease which often presents at an advanced stage. Despite trimodal therapy, 40–50% patients can develop metastatic disease by 18 months. Identification of patients at risk for metastatic spread is challenging with need for improved prognostication. We investigated whether the immune landscape of pretreatment tissue was associated with relapse in ESC patients.

Methods

Between April 2010 and October 2018, we identified 25 patients who had undergone trimodal therapy for ESC and had pretreatment biopsies suitable for analyses. We performed high-throughput multispectral immunofluorescence (mIF) analysis on formalin-fixed paraffin embedded biopsy samples. Analysis of 27 unique populations via immune and exhaustion mIF panels was performed and expression was normalized to total cell counts.

Results

Of the 25 patients analyzed, the median follow-up time was 23.9 months, during which 12 (48%) patients suffered a relapse with a median time to progression of 13.1 months. mIF revealed higher expression of HLA-DR (p = 0.019), CD8/LAG3 (p = 0.046), and CD8/CTLA4 (p = 0.027) among patients without relapse. Time to progression (TTP) and disease-specific survival (DSS) were stratified by median expression of each significant subpopulation and formally tested by the log-rank test. Higher than median expression of HLA-DR (p = 0.027), CD8/LAG3 (p = 0.039), and CD8/CTLA4 (p = 0.039) were significantly associated with TTP. Similarly, HLA-DR (p = 0.0069) and CD8/CTLA4 (p = 0.036) were significantly associated with improved DSS, whereas no significant observations were found with CD8/LAG3 (p = 0.11) expression. Stromal, but not tumoral expression of CD163 and CD163/PDL1 were significantly associated with improved TTP and DSS.

Conclusions

High expression of HLA-DR, CD8/CTLA4, and stromal expression of CD163 and CD163/PDL1 within pretreatment biopsy ESC samples was associated with significantly reduced rates of relapse. Increased presence of these markers suggests that an improved immune landscape is associated with less aggressive disease and may provide an opportunity for risk-based treatment strategies.
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Literature
1.
go back to reference Network NCC (2024) Esophageal and esophagogastric junction cancers. NCCN.org; 03/26/2024 Network NCC (2024) Esophageal and esophagogastric junction cancers. NCCN.org; 03/26/2024
2.
go back to reference Kelly RJ, Ajani JA, Kuzdzal J et al (2021) Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384(13):1191–1203CrossRefPubMed Kelly RJ, Ajani JA, Kuzdzal J et al (2021) Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384(13):1191–1203CrossRefPubMed
3.
go back to reference Lonie JM, Barbour AP, Dolcetti R (2021) Understanding the immuno-biology of oesophageal adenocarcinoma: towards improved therapeutic approaches. Cancer Treat Rev 98:102219CrossRefPubMed Lonie JM, Barbour AP, Dolcetti R (2021) Understanding the immuno-biology of oesophageal adenocarcinoma: towards improved therapeutic approaches. Cancer Treat Rev 98:102219CrossRefPubMed
4.
go back to reference Farrugia MK, Ma SJ, Mattson DM, Flaherty L, Repasky EA, Singh AK (2020) Concurrent beta-blocker use is associated with improved outcome in esophageal cancer patients who undergo chemoradiation: a retrospective matched-pair analysis. Am J Clin Oncol 108(3):619 Farrugia MK, Ma SJ, Mattson DM, Flaherty L, Repasky EA, Singh AK (2020) Concurrent beta-blocker use is associated with improved outcome in esophageal cancer patients who undergo chemoradiation: a retrospective matched-pair analysis. Am J Clin Oncol 108(3):619
5.
go back to reference Derks S, de Klerk LK, Xu X et al (2020) Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas. Ann Oncol 31(8):1011–1020CrossRefPubMed Derks S, de Klerk LK, Xu X et al (2020) Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas. Ann Oncol 31(8):1011–1020CrossRefPubMed
6.
go back to reference van den Ende T, Ezdoglian A, Baas LM et al (2023) Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with Neoadjuvant PD-L1 checkpoint inhibition. Oncoimmunology 12(1):2233403CrossRefPubMedPubMedCentral van den Ende T, Ezdoglian A, Baas LM et al (2023) Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with Neoadjuvant PD-L1 checkpoint inhibition. Oncoimmunology 12(1):2233403CrossRefPubMedPubMedCentral
7.
go back to reference Gobel HH, Buttner-Herold MJ, Fuhrich N, Aigner T, Grabenbauer GG, Distel LVR (2020) Cytotoxic and immunosuppressive inflammatory cells predict regression and prognosis following neoadjuvant radiochemotherapy of oesophageal adenocarcinoma. Radiother Oncol 146:151–160CrossRefPubMed Gobel HH, Buttner-Herold MJ, Fuhrich N, Aigner T, Grabenbauer GG, Distel LVR (2020) Cytotoxic and immunosuppressive inflammatory cells predict regression and prognosis following neoadjuvant radiochemotherapy of oesophageal adenocarcinoma. Radiother Oncol 146:151–160CrossRefPubMed
8.
go back to reference Goedegebuure RSA, Harrasser M, de Klerk LK et al (2021) Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma. Oncoimmunology 10(1):1954807CrossRefPubMedPubMedCentral Goedegebuure RSA, Harrasser M, de Klerk LK et al (2021) Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma. Oncoimmunology 10(1):1954807CrossRefPubMedPubMedCentral
9.
go back to reference Lonie JM, Brosda S, Bonazzi VF et al (2023) The oesophageal adenocarcinoma tumour immune microenvironment dictates outcomes with different modalities of neoadjuvant therapy—results from the AGITG DOCTOR trial and the cancer evolution biobank. Front Immunol 14:1220129CrossRefPubMedPubMedCentral Lonie JM, Brosda S, Bonazzi VF et al (2023) The oesophageal adenocarcinoma tumour immune microenvironment dictates outcomes with different modalities of neoadjuvant therapy—results from the AGITG DOCTOR trial and the cancer evolution biobank. Front Immunol 14:1220129CrossRefPubMedPubMedCentral
10.
go back to reference Dunne MR, Michielsen AJ, O’Sullivan KE et al (2017) HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients. Cancer Immunol Immunother 66(7):841–850CrossRefPubMedPubMedCentral Dunne MR, Michielsen AJ, O’Sullivan KE et al (2017) HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients. Cancer Immunol Immunother 66(7):841–850CrossRefPubMedPubMedCentral
11.
go back to reference Miura Y, Anami T, Yatsuda J et al (2021) HLA-DR and CD74 expression and the immune microenvironment in renal cell carcinoma. Anticancer Res 41(6):2841–2848CrossRefPubMed Miura Y, Anami T, Yatsuda J et al (2021) HLA-DR and CD74 expression and the immune microenvironment in renal cell carcinoma. Anticancer Res 41(6):2841–2848CrossRefPubMed
12.
go back to reference Dunne MR, Phelan JJ, Michielsen AJ et al (2020) Characterising the prognostic potential of HLA-DR during colorectal cancer development. Cancer Immunol Immunother 69(8):1577–1588CrossRefPubMedPubMedCentral Dunne MR, Phelan JJ, Michielsen AJ et al (2020) Characterising the prognostic potential of HLA-DR during colorectal cancer development. Cancer Immunol Immunother 69(8):1577–1588CrossRefPubMedPubMedCentral
13.
go back to reference Heng Y, Zhu X, Wu Q et al (2023) High expression of tumor HLA-DR predicts better prognosis and response to Anti-PD-1 therapy in laryngeal squamous cell carcinoma. Transl Oncol 33:101678CrossRefPubMedPubMedCentral Heng Y, Zhu X, Wu Q et al (2023) High expression of tumor HLA-DR predicts better prognosis and response to Anti-PD-1 therapy in laryngeal squamous cell carcinoma. Transl Oncol 33:101678CrossRefPubMedPubMedCentral
14.
go back to reference Arbore G, Albarello L, Bucci G et al (2023) Preexisting immunity drives the response to neoadjuvant chemotherapy in esophageal adenocarcinoma. Cancer Res 83(17):2873–2888CrossRefPubMedPubMedCentral Arbore G, Albarello L, Bucci G et al (2023) Preexisting immunity drives the response to neoadjuvant chemotherapy in esophageal adenocarcinoma. Cancer Res 83(17):2873–2888CrossRefPubMedPubMedCentral
15.
go back to reference Perez-Garcia A, Osca G, Bosch-Vizcaya A et al (2013) Kinetics of the CTLA-4 isoforms expression after T-lymphocyte activation and role of the promoter polymorphisms on CTLA-4 gene transcription. Hum Immunol 74(9):1219–1224CrossRefPubMed Perez-Garcia A, Osca G, Bosch-Vizcaya A et al (2013) Kinetics of the CTLA-4 isoforms expression after T-lymphocyte activation and role of the promoter polymorphisms on CTLA-4 gene transcription. Hum Immunol 74(9):1219–1224CrossRefPubMed
17.
go back to reference Wang W, Chen D, Zhao Y et al (2019) Characterization of LAG-3, CTLA-4, and CD8(+) TIL density and their joint influence on the prognosis of patients with esophageal squamous cell carcinoma. Ann Transl Med 7(23):776CrossRefPubMedPubMedCentral Wang W, Chen D, Zhao Y et al (2019) Characterization of LAG-3, CTLA-4, and CD8(+) TIL density and their joint influence on the prognosis of patients with esophageal squamous cell carcinoma. Ann Transl Med 7(23):776CrossRefPubMedPubMedCentral
18.
go back to reference Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J (2015) Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: implications for prognosis. Cancer Immunol Immunother 64(7):853–860CrossRefPubMedPubMedCentral Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J (2015) Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: implications for prognosis. Cancer Immunol Immunother 64(7):853–860CrossRefPubMedPubMedCentral
19.
go back to reference Wilk BJ, Eyck BM, Wijnhoven BPL et al (2023) Neoadjuvant chemoradiotherapy followed by surgery versus active surveillance for oesophageal cancer (SANO-trial): a phase-III stepped-wedge cluster randomised trial. Ann Oncol 34:S1317CrossRef Wilk BJ, Eyck BM, Wijnhoven BPL et al (2023) Neoadjuvant chemoradiotherapy followed by surgery versus active surveillance for oesophageal cancer (SANO-trial): a phase-III stepped-wedge cluster randomised trial. Ann Oncol 34:S1317CrossRef
20.
go back to reference Takeda FR, Tustumi F, de Almeida OC et al (2020) Prognostic value of tumor regression grade based on ryan score in squamous cell carcinoma and adenocarcinoma of esophagus. Ann Surg Oncol 27(4):1241–1247CrossRefPubMed Takeda FR, Tustumi F, de Almeida OC et al (2020) Prognostic value of tumor regression grade based on ryan score in squamous cell carcinoma and adenocarcinoma of esophagus. Ann Surg Oncol 27(4):1241–1247CrossRefPubMed
21.
go back to reference Zhang C, Xu F, Qiang Y et al (2022) Prognostic significance of tumor regression grade in esophageal squamous cell carcinoma after neoadjuvant chemoradiation. Front Surg 9:1029575CrossRefPubMed Zhang C, Xu F, Qiang Y et al (2022) Prognostic significance of tumor regression grade in esophageal squamous cell carcinoma after neoadjuvant chemoradiation. Front Surg 9:1029575CrossRefPubMed
Metadata
Title
Prognostic immune markers in esophageal cancer patients managed with trimodal therapy
Authors
Mark K. Farrugia
Elizabeth A. Repasky
Minhui Chen
Kristopher Attwood
Kayla Catalfamo
Hanna Rosenheck
Song Yao
David M. Mattson
Sarbajit Mukherjee
Moshim Kukar
Agnieszka K. Witkiewicz
Anurag K. Singh
Publication date
01-02-2025
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 2/2025
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-024-03891-3

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