High CCR4 expression in the tumor microenvironment is a poor prognostic indicator in lung adenocarcinoma

Takahiro Karasaki, Guangliang Qiang, Masaki Anraku, Yanbin Sun, Aya Shinozaki-Ushiku, Eiichi Sato, Kosuke Kashiwabara, Kazuhiro Nagayama, Jun-ichi Nitadori, Masaaki Sato, Tomohiro Murakawa, Kazuhiro Kakimi, Masashi Fukayama, Jun Nakajima


Background: Clinical trials of anti-CCR4 antibody for solid cancers with or without other immune-modulating agents including immune checkpoint blockade therapy are currently underway. However, little is known about the roles of CCR4+ lymphocytes and their prognostic impact in lung cancer. We hypothesized that high CCR4 expression in the tumor microenvironment would be associated with a poor prognosis and would act as a biomarker in lung adenocarcinoma.
Methods: First, the prognostic impact of CCR4 gene expression was explored using pooled data from public transcriptomic databases with online survival analysis software. Second, tissue microarrays (TMAs) were constructed from resected lung adenocarcinoma specimens from tumors up to 3 cm in size. The density of CCR4+ lymphocytes infiltrating the tumor was then assessed by immunohistochemistry and related to survival. Confounding factors were controlled for by multivariate analysis using the Cox proportional hazards model.
Results: Higher than median expression of the CCR4 gene was identified as an independent poor prognostic factor for overall survival (OS) by multivariate analysis of 720 lung adenocarcinoma patients in the public databases [HR =1.55 (95% CI: 1.03–2.35), P=0.037]. Consistent with this, high CCR4+ tumor-infiltrating lymphocyte (TIL) density was found to be an independent poor prognostic factor for both OS [HR =2.24 (1.01–5.34), P=0.049] and recurrence-free survival (RFS) [HR =2.20 (1.16–4.39), P=0.017] in the patients from whom TMA were obtained (n=180). Age, male gender, predominantly non-lepidic histological subtype, nodal involvement, and low CD8+ TIL density were also independent poor prognostic factors. However, FOXP3 gene expression and Foxp3+ lymphocyte infiltration did not possess any prognostic value in either study.
Conclusions: High CCR4 expression in the tumor microenvironment may be a poor prognostic factor in lung adenocarcinoma. Patients with high CCR4+ lymphocyte infiltration may have a poor prognosis and thus be suitable candidates for clinical trials of anti-CCR4 antibody treatment.