Clinical significance of CD8+ and FoxP3+ tumor-infiltrating lymphocytes and MFG-E8 expression in lower rectal cancer with preoperative chemoradiotherapy

Yuzo Harada; Shinsuke Kazama; Teppei Morikawa; Hirofumi Sonoda; Hiroaki Ishi; Shigenobu Emoto; Koji Murono; Manabu Kaneko; Kazuhito Sasaki; Yasutaka Shuno; Takeshi Nishikawa; Toshiaki Tanaka; Kazushige Kawai; Keisuke Hata; Hiroaki Nozawa; Tetsuo Ushiku; Hideaki Tahara; Soichiro Ishihara

doi:10.3892/mco.2021.2249

Clinical significance of CD8⁺ and FoxP3⁺ tumor-infiltrating lymphocytes and MFG-E8 expression in lower rectal cancer with preoperative chemoradiotherapy

Mol Clin Oncol. 2021 May;14(5):87. doi: 10.3892/mco.2021.2249. Epub 2021 Mar 5.

Authors

Yuzo Harada¹, Shinsuke Kazama^{1

2}, Teppei Morikawa³, Hirofumi Sonoda¹, Hiroaki Ishi¹, Shigenobu Emoto¹, Koji Murono¹, Manabu Kaneko¹, Kazuhito Sasaki¹, Yasutaka Shuno¹, Takeshi Nishikawa¹, Toshiaki Tanaka¹, Kazushige Kawai¹, Keisuke Hata¹, Hiroaki Nozawa¹, Tetsuo Ushiku⁴, Hideaki Tahara^{5

6}, Soichiro Ishihara¹

Affiliations

¹ Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
² Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama 362-0806, Japan.
³ Department of Pathology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan.
⁴ Department of Pathology, The University of Tokyo, Tokyo 113-8655, Japan.
⁵ Project Division of Cancer Biomolecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁶ Department of Cancer Drug Discovery and Development Project, Osaka International Cancer Institute, Osaka 541-8567, Japan.

Abstract

Preoperative chemoradiotherapy (CRT) for rectal cancer contributes to tumor down-staging and decreases locoregional recurrence. However, each patient shows a significantly different response to CRT. Therefore, the identification of predictive factors to CRT response would be beneficial to avoid unnecessary treatment. Cancer immunity in patients has been suggested to play an important role in the eradication of the tumor by CRT. In the present study, the utility of CD8⁺ and forkhead box P3 (FoxP3)⁺ tumor-infiltrating lymphocytes (TILs) and the expression of a novel immuno-regulatory factor, lactadherin (MFG-E8), in predicting CRT effectiveness in patients with rectal cancer was examined. A total of 61 patients with rectal cancer, who underwent curative resection following CRT were included in the study. The numbers of CD8⁺ and FoxP3⁺ TILs in a biopsy taken before CRT and MFG-E8 expression level in the specimens obtained at the time of the surgery after CRT were examined using immunohistochemical staining, and their association with clinicopathological characteristics, including patient survival, was determined. The tumors with more CD8⁺ TILs in the biopsy samples before CRT showed a significantly more favorable CRT response. The patients with tumors and a higher number of CD8⁺ TILs before CRT also exhibited significantly longer disease-free and overall survival times. Higher MFG-E8 expression level in post-CRT specimens was significantly associated with favorable CRT response; however, no significant association was found with any other clinicopathological characteristics, including survival time. The number of CD8⁺ TILs before CRT was a valuable predictor for CRT response and was associated with favorable prognosis in patients with lower rectal cancer and who were treated with CRT. High MFG-E8 expression level after CRT was also associated with a favorable CRT response.

Keywords: CD8+ TIL; FoxP3+ TIL; MFG-E8; chemoradiotherapy; immunohistochemistry; rectal cancer.

Grants and funding

Funding: This research was supported by Grants-in-Aid for Scientific Research (A: Grant no. 16H02672, C: Grant nos. 16K07143, 16K07161, 17K10620, 10621 and 17K10623) from the Japan Society for the Promotion of Science and by the Project for Cancer Research and Therapeutic Evolution (grant no. 16cm0106502h0001) from the Japan Agency for Medical Research and Development.