Skip to main content
SpringerLink
Log in

The Immunological Impact of Neoadjuvant Chemotherapy on the Tumor Microenvironment of Esophageal Squamous Cell Carcinoma

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Esophageal cancer is an aggressive cancer with poor prognosis. However, little is known about the immune response in the tumor microenvironment after neoadjuvant chemotherapy.

Purpose

To investigate the immunological impact of neoadjuvant chemotherapy in the tumor microenvironment of esophageal squamous cell carcinoma.

Methods

Eighteen patients with esophageal squamous cell carcinoma with and without neoadjuvant chemotherapy were analyzed using immunohistochemical methods for human leukocyte antigen (HLA) class I heavy chain, CD4-, CD8-, and Foxp3-positive cell infiltration.

Results

The number of CD4 T cells in the stroma and within the cancer nest was significantly higher in the neoadjuvant chemotherapy group. The number of CD8 T cells in the stroma was significantly higher in the neoadjuvant chemotherapy group. HLA class I expression was more downregulated in the control group compared with the neoadjuvant chemotherapy group.

Conclusion

Neoadjuvant chemotherapy utilizing 5-fluorouracil and cisplatin in esophageal squamous cell carcinoma is useful to induce CD4 and CD8 T lymphocytes in the tumor microenvironment and to maintain HLA class I expression levels in combination with its direct cytotoxic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study—JCOG9204. J Clin Oncol. 2003;21:4592–6.

    Article  PubMed  Google Scholar 

  2. Campbell NP, Villaflor VM. Neoadjuvant treatment of esophageal cancer. World J Gastroenterol. 2010;16:3793–803.

    Article  PubMed  CAS  Google Scholar 

  3. Higuchi K, Koizumi W, Tanabe S, et al. Current management of esophageal squamous-cell carcinoma in Japan and other countries. Gastrointest Cancer Res. 2009;3:153–61.

    PubMed  Google Scholar 

  4. Cho Y, Miyamoto M, Kato K, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res. 2003;63:1555–9.

    PubMed  CAS  Google Scholar 

  5. Yoshioka T, Miyamoto M, Cho Y, et al. Infiltrating regulatory T cell numbers is not a factor to predict patient’s survival in oesophageal squamous cell carcinoma. Br J Cancer. 2008;98:1258–63.

    Article  PubMed  CAS  Google Scholar 

  6. Canna K, Hilmy M, McMillan DC, Smith GW, McKee RF, McArdle CS, et al. The relationship between tumour proliferative activity, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Colorectal Dis. 2008;10:663–7.

    Article  PubMed  CAS  Google Scholar 

  7. McMillan DC, Canna K, McArdle CS. Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg. 2003;90:215–9.

    Article  PubMed  CAS  Google Scholar 

  8. Sobin LH, Wittekind Ch. International Union Against Cancer. TNM classification of malignant tumors. New York: Wiley-Liss; 2002. P. 60–4.

    Google Scholar 

  9. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.

    Article  PubMed  CAS  Google Scholar 

  10. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127:1335–9.

    Article  PubMed  CAS  Google Scholar 

  11. Wada S, Yoshimura K, Hipkiss EL, et al. Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model. Cancer Res. 2009;69:4309–18.

    Article  PubMed  CAS  Google Scholar 

  12. Garnett CT, Schlom J, Hodge JW. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin Cancer Res. 2008;14:3536–44.

    Article  PubMed  CAS  Google Scholar 

  13. Rozková D, Tiserová H, Fucíková J, et al. FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer. Clin Immunol. 2009;131:1–10.

    Article  PubMed  Google Scholar 

  14. Lesterhuis WJ, de Vries IJ, Aarntzen EA, et al. A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients. Br J Cancer. 2010;103:1415–21.

    Article  PubMed  CAS  Google Scholar 

  15. Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61.

    Article  PubMed  CAS  Google Scholar 

  16. Obeid M, Tesniere A, Panaretakis T, et al. Ecto-calreticulin in immunogenic chemotherapy. Immunol Rev. 2007;220:22–34.

    Article  PubMed  CAS  Google Scholar 

  17. Chaput N, De Botton S, Obeid M, et al. Molecular determinants of immunogenic cell death: surface exposure of calreticulin makes the difference. J Mol Med. 2007;85:1069–76.

    Article  PubMed  CAS  Google Scholar 

  18. Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 2010;28:367–88.

    Article  PubMed  CAS  Google Scholar 

  19. Brode S, Cooke A. Immune-potentiating effects of the chemotherapeutic drug cyclophosphamide. Crit Rev Immunol. 2008;28:109–26.

    PubMed  CAS  Google Scholar 

  20. Schnurr M, Chen Q, Shin A, et al. Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. Blood. 2005;105:2465–72.

    Article  PubMed  CAS  Google Scholar 

  21. Ladányi A, Kiss J, Somlai B, et al. Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother. 2007;56:1459–69.

    Article  PubMed  Google Scholar 

  22. Bembenek A, Li J, Loddenkemper C, Kemmner W, Stein H, Wernecke KD, et al. Presence of mature DC-Lamp+ dendritic cells in sentinel and non-sentinel lymph nodes of breast cancer patients. Eur J Surg Oncol. 2008;34:514–8.

    Article  PubMed  CAS  Google Scholar 

  23. Rauser S, Langer R, Tschernitz S, et al. High number of CD45RO+ tumor infiltrating lymphocytes is an independent prognostic factor in non-metastasized (stage I-IIA) esophageal adenocarcinoma. BMC Cancer. 2010;10:608–16.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We appreciate Hiraku Shida for his technical assistance in immunohistochemistry.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Takahiro Tsuchikawa MD, Masaki Miyamoto MD, Yoshiyuki Yamamura MD, Toshiaki Shichinohe MD, Satoshi Hirano MD & Satoshi Kondo MD

Authors
  1. Takahiro Tsuchikawa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masaki Miyamoto MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshiyuki Yamamura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiaki Shichinohe MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoshi Hirano MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Kondo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takahiro Tsuchikawa MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsuchikawa, T., MD, M.M., Yamamura, Y. et al. The Immunological Impact of Neoadjuvant Chemotherapy on the Tumor Microenvironment of Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 19, 1713–1719 (2012). https://doi.org/10.1245/s10434-011-1906-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-011-1906-x

Keywords

Search

Navigation