Density of Tumor-Infiltrating FOXP3+ T Cells as a Response Marker for Induction Chemoradiotherapy and a Potential Prognostic Factor in Patients Treated with Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer

Tao, Hiroyuki; Shien, Kazuhiko; Soh, Junichi; Matsuda, Eriko; Toyooka, Shinichi; Okabe, Kazunori; Miyoshi, Shinichiro

doi:10.5761/atcs.oa.13-00237

Cited by 9 publications

(7 citation statements)

References 31 publications

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“…FOXP3 expression in Treg cells could also be seen in NSCLC specimens. Although Treg cells in NSCLC were reported with poor prognosis in some publications [30, 31]. However, we did not find its prognostic value in NSCLC.…”

Section: Discussioncontrasting

confidence: 79%

FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer

et al. 2017

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BackgroundThe role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC).MethodsOne hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results.ResultsNSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial–mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction.ConclusionsFOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0700-1) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 79%

FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer

et al. 2017

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“…These studies were published between 2003 and 2015. Six studies [ 21 , 25 , 30 , 35 , 37 , 38 ] concerned CD3 + T lymphocytes, six studies [ 14 , 16 , 19 , 22 , 28 , 33 ] were of CD4 + T lymphocytes, and six studies reported on FoxP3 + T lymphocytes [ 13 , 21 , 27 , 31 , 33 , 34 ]. The TILs ratio was reported in five studies, including both CD4 + /CD8 + ratio [ 16 , 22 , 32 ] and FoxP3 + /CD3 + ratio [ 13 , 21 ], and 16 studies [ 14 – 16 , 19 , 20 , 22 – 24 , 26 , 28 , 29 , 33 , 35 – 38 ] considered CD8 + T lymphocytes, which was the most popular lymphocyte marker.…”

Section: Resultsmentioning

confidence: 99%

“…Kawai et al [ 23 ] reported that higher CD8 + infiltration within the tumor nest after platinum-based chemotherapy was strongly associated with better overall survival in patients with stage IV NSCLC. Tao et al [ 34 ] demonstrated that a low density of FoxP3 + TILs indicated a better response to induction chemoradiation and better survival in locally advanced NSCLC, although the difference was not statistically significant, suggesting that FoxP3 + TILs might be a target for adjunct immunotherapy. Furthermore, cytotoxic CD8 + T cells are crucial in novel therapies targeting the immune system, e.g., by blocking CD8 T cell-related ligands (PD-L1 and PD-L2) and receptors (PD-1 and CTLA-4), antitumor immunity is enhanced in patients with various types of advanced solid tumors, including NSCLC [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer

et al. 2016

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BackgroundPrevious preclinical and clinical studies have shown that levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in non-small cell lung cancer (NSCLC), and survival after therapy; however, this finding remains controversial. We performed a meta-analysis, to evaluate, systematically, the clinical utilization of TIL subtypes in patients with NSCLC.MethodsThe PubMed, ISI Web of Science, EMBASE, and Cochrane Library databases were searched to identify relevant studies. We pooled estimates of treatment effects, and hazards were summarized using random or fixed effects models to evaluate survival outcomes.ResultsA total of 24 relevant studies involving 7,006 patients were eligible. The median percentage of lymph node positivity was 45.7% (95% confidence interval [CI], 37.1–56.4%). Pooled analysis shows that high levels of CD8+ TILs had a good prognostic effect on survival with a hazard ratio (HR) of 0.91 (P = 0.013) for death and 0.74 (P = 0.001) for recurrence, as did high levels of CD3+ and CD4+ TILs, with HRs of 0.77 (P = 0.009) and 0.78 (P = 0.005) for death, respectively. By contrast, high levels of FoxP3+ regulatory TILs had a worse prognostic effect for overall and recurrence-free survival, with HRs of 1.69 (P = 0.042) and 1.79 (P = 0.001), respectively. No individual study affected the results, and no publication bias was found.ConclusionsOur findings support the hypothesis that TILs could be a prognostic marker in NSCLC. High-quality randomized studies are needed to verify statistically the effect of TILs on prognosis in future research.

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“…Nevertheless, there is substantial heterogeneity in the methodology and reproducibility of these findings. [ 7 , 8 , 11 , 12 , 15 – 26 ] There is also substantial debate regarding the spatial locations of the immune infiltrates and its correlate with survival with some authors suggesting stromal infiltrates being more prognostic, others suggesting tumoral infiltrates and more recently data suggesting the immune interface at the invasive margin as being most prognostic. [ 7 , 18 , 27 ]…”

Section: Introductionmentioning

confidence: 99%

PD-L1 and Tumor Infiltrating Lymphocytes as Prognostic Markers in Resected NSCLC

et al. 2016

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IntroductionImmune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC.MethodsA tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression.ResultsOf 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36–0.94, p = 0.031; HR 0.46, 95%CI 0.26–0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50–0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%).ConclusionPD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation.

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Density of Tumor-Infiltrating FOXP3+ T Cells as a Response Marker for Induction Chemoradiotherapy and a Potential Prognostic Factor in Patients Treated with Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer

Cited by 9 publications

References 31 publications

FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer

FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer

Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer

PD-L1 and Tumor Infiltrating Lymphocytes as Prognostic Markers in Resected NSCLC

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