Combined Evaluation of Tumor-Infiltrating CD8 + and FoxP3 + Lymphocytes Provides Accurate Prognosis in Stage IA Lung Adenocarcinoma

Fumihiko Kinoshita MD, Kazuki Takada MD, PhD, Yuichi Yamada MD, PhD, Yuka Oku MD, Keisuke Kosai MD, Yuki Ono MD, Kensuke Tanaka MD, Sho Wakasu MD, Taro Oba MD, PhD, Atsushi Osoegawa MD, PhD, Tetsuzo Tagawa MD, PhD, Mototsugu Shimokawa PhD, Yoshinao Oda MD, PhD, Masaki Mori MD, PhD
Translational Research and Biomarkers
Online First ™ - November , 2019

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Abstract

Background

Immunotherapy has become a standard treatment option for non-small cell lung cancer (NSCLC), with the tumor microenvironment attracting significant attention. CD8 + and forkhead box protein P3 + (FoxP3 +) tumor-infiltrating lymphocytes (TILs) influence the tumor microenvironment, but the clinical significance of CD8 + and FoxP3 + TILs in stage IA lung adenocarcinoma (LAD) is poorly understood.

Methods

We analyzed 203 patients with stage IA primary LAD who had undergone surgery at Kyushu University from January 2003 to December 2012. We evaluated CD8 + and FoxP3 + TILs by immunohistochemistry. We set the cutoff values at 50 cells/0.04 mm² for CD8 + TILs and 20 cells/0.04 mm² for FoxP3 + TILs, respectively. We divided the patients into four groups: CD8-Low/FoxP3-Low; CD8-High/FoxP3-Low; CD8-Low/FoxP3-High; and CD8-High/FoxP3-High. We compared clinical outcomes among them. Programmed cell death ligand-1 (PD-L1) expression by tumor cells was also evaluated as previously reported.

Results

Respectively, 104 (51.2%), 46 (22.7%), 22 (10.8%), and 31 (15.3%) patients were classified as CD8-Low/FoxP3-Low, CD8-High/FoxP3-Low, CD8-Low/FoxP3-High, and CD8-High/FoxP3-High. Both disease-free survival (DFS) and overall survival (OS) were significantly worse in the CD8-Low/FoxP3-High group than the other groups (5-year DFS: 66.3% vs. 90.5%; P = 0.0007, 5-year OS: 90.9% vs. 97.0%; P = 0.0077). In the multivariate analysis, CD8-Low/FoxP3-High and PD-L1 expression were independent prognostic factors of DFS, and lymphatic invasion, surgical procedure, and PD-L1 expression were independent prognostic factors of OS.

Conclusions

CD8-Low/FoxP3-High was an independent prognostic factor of DFS (hazard ratio: 3.22; 95% confidence interval: 1.321–7.179; P = 0.0121) in stage IA LAD. Immunosuppressive conditions were associated with poor prognosis in stage IA LAD.

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