Research Papers:

Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma

Ken Hatogai, Shigehisa Kitano, Satoshi Fujii, Takashi Kojima, Hiroyuki Daiko, Shogo Nomura, Takayuki Yoshino, Atsushi Ohtsu, Yuichi Takiguchi, Toshihiko Doi and Atsushi Ochiai _

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Oncotarget. 2016; 7:47252-47264. https://doi.org/10.18632/oncotarget.10055

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Ken Hatogai1,2,3, Shigehisa Kitano4, Satoshi Fujii1, Takashi Kojima2, Hiroyuki Daiko5, Shogo Nomura6, Takayuki Yoshino2, Atsushi Ohtsu2,7, Yuichi Takiguchi3, Toshihiko Doi2, Atsushi Ochiai1

1Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan

2Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

3Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan

4Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan

5Department of Esophageal Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

6Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Kashiwa, Japan

7Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan

Correspondence to:

Atsushi Ochiai, email: [email protected]

Keywords: esophageal cancer, immunohistochemistry, PD-L1, tumor infiltrating lymphocyte, macrophage

Received: December 31, 2015     Accepted: June 04, 2016     Published: June 15, 2016


Immunotherapy with anti-PD-1 antibody preliminarily showed promising efficacy for treating esophageal squamous cell carcinoma (ESCC). Herein, we used tissue microarrays and immunohistochemically analyzed PD-L1 and various tumor infiltrating immune cells (TIICs) in specimens from 196 ESCC patients who had undergone curative resection without preoperative therapy. PD-L1 expressions in tumor cells (TCs) and TIICs, as well as infiltration of lymphocytes (CD4+, CD8+, FOXP3+, and PD- 1+) and macrophages (CD68+ and CD204+), were evaluated. PD-L1 was expressed in TCs of 18.4% and in TIICs of 83.3% of these patients. PD-L1 expressions in TCs and TIICs were associated with significant infiltration of various TIIC types, especially CD8+ cells. PD-L1 expressions in both TCs and TIICs were significantly associated with favorable overall survival, and combining their levels enhanced prognostic accuracy. Prognostic impacts of PD-L1 expressions in TCs and TIICs, abundant PD-1+ cell infiltration, a high CD8+/FOXP3+ ratio, and the CD8+/CD204+ ratio remained significant after adjusting for clinicopathological factors. In conclusion, PD-L1 expression reflects anti-tumor immunity, and PD-1/PD-L1 expression and the ratio of infiltrating effector to immune suppressor cells have prognostic value. Therapeutic strategies inhibiting the PD-1/PD-L1 signal and immune suppressor cells are anticipated in ESCC patients.

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