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M. Usó



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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.02 - Tumor and Stroma Treg markers in resectable NSCLC (ID 2753)

      16:15 - 17:45  |  Author(s): M. Usó

      • Abstract
      • Presentation
      • Slides

      Background
      Immunosuppressive regulatory T lymphocytes (Tregs) have been proved to play a critical role in immune tolerance to tumor. In this study we have analyzed several markers related to Tregs, in both tumor and stroma areas in patients with resectable NSCLC.

      Methods
      Tumor FFPE samples from 135 early-stage NSCLC patients were used in this retrospective study. The most representative areas of tumor cells and tumor stroma of each sample were carefully micro-dissected. RTqPCR using hydrolysis probes was performed to determine the expression of Treg markers such as: CD127, CD25, FOXP3, CTLA-4, IL-10, TGFB-1, LAG-3, GITR and TNF-a as well as CD4 and CD8. Relative gene expression was assessed using GAPDH and CDKN1B as endogenous controls and results were normalized against a human cDNA as a reference. FOXP3 protein expression was assessed by immunohistochemistry, in 80 of the 135 patients included in this study. The absolute number of FOXP3-positive lymphocytes was determined in both tumor and stroma areas by averaging the cell counts in 10 fields (400X). All statistical analyses were considered significant at p< 0.05.

      Results
      Gene expression analyses revealed an over-expression of CD25 (5.40X and 7.95X, respectively) and down-expression of CD127 (0.28X and 0.37X, respectively) in both, tumor and stroma. There was a tendency toward higher expression of FOXP3 (1.67X and 2.01X, respectively) and CTLA-4 (1.92X and 1.76X, respectively) as well. Paired Wilcoxon test showed significant gene expression differences between tumor and stroma in FOXP3 (p=0.006), CD25 (p<0.0001), CD4 (p<0.0001), CD8 (p=0.028), IL-10 (p<0.0001) and TGFB-1 (p<0.0001). Survival analyses revealed that patients with a “Treg profile” (↑CD25/↓CD127) had a reduced overall survival (OS), whilst those patients with higher levels of the ratio FOXP3 stroma/tumor had worse time to progression (TTP) (Table 1). Spearman test revealed a significant association between stromal FOXP3 expression levels and the number of FOXP3-positive lymphocytes (by IHC) in stroma, p=0.006. Moreover, chi-square test showed that patients with squamous cell carcinoma histology presented a higher number of FOXP3-positive lymphocytes than those patients with adenocarcinoma, p= 0.035. Table 1: OS for “Treg profile” and TTP for Ratio FOXP3 Stroma/Tumor

      OS
      Median (months) 95% CI p
      Others 74.33 65.96 - 82.69 0.003
      "Treg profile" 29.90 4.91 - 6.54
      TTP
      Median (months) 95% CI p
      ↓ Ratio FOXP3 Stroma/Tumor NR -- 0.040
      ↑ Ratio FOXP3 Stroma/Tumor 32.50 16.25- 48.74

      Conclusion
      Gene expression of Treg markers in tumor microenvironment seem to play an important prognostic role in early-stage NSCLC patients. Furthermore, preliminary IHC analysis indicated a correlation between mRNA and protein levels for FOXP3 in NSCLC patients. Supported in part, by grants PS09/01149, RD06/0020/1024 and RD12/0036/0025 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III (ISCIII).

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-037 - Expression of stemness factors OCT4 and NANOG in resectable non-small cell lung cancer. (ID 2695)

      09:30 - 16:30  |  Author(s): M. Usó

      • Abstract

      Background
      Epithelial–mesenchymal transition (EMT) and expression of stemness features are key issues for tissue invasion and metastasis during cancer development. OCT4 and NANOG are homebox transcription factors essential to the self-renewal of stem cells and are expressed in several cancers. The role of OCT4/NANOG signaling in tumorigenesis and as biomarkers in non-small cell lung cancer (NSCLC) is still elusive.

      Methods
      mRNA was isolated from 177 frozen samples, corresponding to tumoral and normal parenchyma of NSCLC patients in resectable-stage. OCT4 and NANOG relative expression was determined by RTqPCR using hydrolysis probes. Expression levels were normalized using GUSB as endogenous housekeeping gene. Statistical significance was considered for p<0.05.

      Results
      Patient’s median age was 64 years [26-87], 87.6 % were males, 75.2 % presented performance status (PS=0) and 47.3% had squamous histology. We found a significant positive correlation between OCT4 and NANOG expression (r[2 ]=0.61 p<0.0001, Pearson test). Higher levels of expression of NANOG were related to poor differentiation grade (p= 0.04). Survival analysis revealed that there is a trend to a poorer progression free survival in the subgroup of patients with higher levels (> median) of expression of OCT4 levels

      Conclusion
      The transcription factor OCT4 may have a role as prognostic biomarker in resectable NSCLC. (Supported in part by ISCIII (PI12/02838), RTICC (RD12/0036/0025), Ministry of Economy and Competitiveness and SEOM Grants 2012)