Foxp3 Expression In Tumor Cells Research Articles

FOXP3 in Melanoma with Regression: Between Tumoral Expression and Regulatory T Cell Upregulation.

Cutaneous melanoma is a significant immunogenic tumoral model, the most frequently described immune phenomenon being tumor regression, as a result of the interaction of tumoral antigens and stromal microenvironment. We present a retrospective cohort study including 52 cases of melanoma with regression. There were evaluated correlations of the most important prognostic factors (Breslow depth and mitotic index) with FOXP3 expression in tumor cells and with the presence of regulatory T cells and dendritic cells in the tumoral stroma. FOXP3 expression in tumor cells seems an independent factor of poor prognosis in melanoma, while regression areas are characterized by a high number of dendritic cells and a low number of regulatory T cells. FOXP3 is probably a useful therapeutical target in melanoma, since inhibition of FOXP3-positive tumor clones and of regulatory T cells could eliminate the ability of tumor cells to escape the immune defense of the host.

Clinical Relevance of the serum CTLA-4 in Cats with Mammary Carcinoma

Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) serves an important role in breast cancer progression, which has led to the development of novel immunotherapies aimed at blocking tumor immune evasion. Although feline mammary carcinoma is increasingly recognized as a valuable cancer model, no studies on CTLA-4 function had been conducted in this species. The serum CTLA-4, TNF-α and IL-6 levels of 57 female cats with mammary carcinoma were determined by ELISA, and immunohistochemistry was performed to evaluate CTLA-4 and FoxP3 expression in tumor cells and interstitial lymphocytes. The results obtained show that serum CTLA-4 levels are increased in cats with mammary carcinoma (P = 0.022), showing an association with a number of clinicopathological features: smaller tumor size, P < 0.001; absence of tumor necrosis, P < 0.001; non-basal status, P < 0.02 and HER-2-positive status. Additionally, a strong positive correlation was found between serum CTLA-4 levels and serum TNF-α (R = 0.88, P < 0.001) and IL-6 levels (R = 0.72, P < 0.001). Concerning the CTLA-4 and FoxP3 expression, although detected in both interstitial lymphocytes and tumor cells, a positive association was found only between interstitial CTLA-4 and FoxP3 expressions (R = 0.387, P = 0.01), which is negatively associated with the serum CTLA-4 levels (P = 0.03). These findings provide a preliminary step in the characterization of immune profiles in feline mammary carcinoma, uncovering a molecular rationale for targeted therapy with CTLA-4 pathway inhibitors. Finally, by strengthening the hypothesis of an immunomodulatory role for this regulator, we further validate the utility of spontaneous feline mammary carcinoma as a model for human breast cancer.

Interaction of cancer cell-derived Foxp3 and tumor microenvironment in human tongue squamous cell carcinoma

The forkhead transcription factor, Foxp3, has been proved essential for differentiation and activation of regulatory T cells (Tregs). Recently, Foxp3 expression in tumor cells (cancer cell-derived Foxp3) has gained increasing interest, but the function has yet to be confirmed. In the current investigation, we identified the interaction of cancer cell-derived Foxp3 and tumor microenvironment in human tongue squamous cell carcinoma(TSCC) by various in vitro methods. We detected cancer cell-derived Foxp3 was closely associated with the infiltration of Foxp3 + lymphocytes in TSCC lesions using immunohistochemical staining. The cytokines secretion (IFN-γ, TGFβ, IL-2, IL-6, IL-1β, IL-10, IL-8, IL-17, IL-23) of PBMC and differentiation of CD4 +T cells were modulated by the expression of Foxp3 in TSCC, shown by ELISA and flow cytometry. As feedback, increasing TGFβ and decreasing IL-17 further up-regulated cancer cell-derived Foxp3. Furthermore, CHIP on chip assay showed that both TGFβ and IL-17 decreased the number of Foxp3-binding genes in TSCC. GO and pathway analysis suggested that, treated with TGFβ or Th17, Foxp3-binding genes were inclined to the negative regulation of TGFβ signal pathway. Taken together, this study showed cancer cell-derived Foxp3 contributed to Tregs expansion in TSCC microenvironment with positive and negative feedbacks.

Expression of Foxp3 and its prognostic significance in colorectal cancer

The aim of this study was to explore the expression and clinical significance of Foxp3 in colorectal tumor cells. An immunohistochemistry assay was used to detect the expression of Foxp3 in 173 cases of colorectal cancer. The relationship between the clinicopathological factors and the prognosis of colorectal cancer was analyzed. The rate of positive Foxp3 expression in tumor cells was 89.7%. There were no significant differences between cases with and without expression of Foxp3 with regard to sex, age, primary cancer sites, and distal metastasis. The expression of Foxp3 was negatively correlated with lymph node metastasis and pathological tumor, node, metastasis (pTNM) stage in tumor cells (P < 0.05), which reflects the depth of invasion. Foxp3 expression also had a positive correlation with the degree of differentiation (P < 0.01). A high level of Foxp3 expression was observed more often in tumor cells compared to tumor-surrounding tissues (P = 0.003). High expression of Foxp3 was also associated with longer overall and disease-free survival (P ⩽ 0.001). Foxp3 expression in colorectal cancer cells correlates with many clinicopathological characteristics; moreover, high expression of Foxp3 may be a promising potential prognostic factor for patients with colorectal cancer.

Abstract 2514: Activity of a novel Foxp3-tumor cell vaccine in a murine model of renal cell carcinoma

Abstract Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and represents 80% of the cases. Treatment options for patients with advanced disease are limited. Targeted molecular therapies have shown survival benefit but most patients develop therapy resistance overtime. Preclinical and clinical studies indicate that immunotherapies are effective and may play a role in the treatment of advanced RCC. However, the response rate is ∼ 20%, with a limited number of patients achieving durable remission. A major barrier to vaccine therapy is the presence of immunosuppressive cell populations including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). In the current study, we designed a tumor cell and Tregs dual-targeting vaccine by inducing Foxp3 expression in tumor cells, and tested this vaccine along with an unmodified vaccine in an orthotopic murine model of RCC, RENCA. We observed that both RENCA cell vaccine and RENCA Foxp3 cell vaccine prevented tumor growth in 6 out 10 animals. Interestingly, in an intervention setting, the RENCA Foxp3 tumor cell vaccine was superior to the RENCA tumor cell vaccine with a significant anti-tumor activity (45% inhibition of tumor weights) (p&amp;lt;0.01). Moreover, RENCA Foxp3 tumor cell vaccine reduced the number of tumor infiltrating Tregs (42% reduction, p&amp;lt;0.05) and Treg Foxp3 expression both in peripheral blood and tumor infiltrates. In summary, our results suggest that a strategy targeting Tregs along with vaccine therapy or a dual targeting vaccine strategy may be beneficial in established RCC. We also observed that suppressive myeloid cell (SMCs) populations dominate the established tumor microenvironment and we are currently testing the combination of the dual-targeting vaccine with a SMC-targeting agent. Citation Format: Li Shen, Ashley Orillion, Remi Adelaiye, Eric Ciamporcero, Swathi Ramakrishnan, Roberto Pili. Activity of a novel Foxp3-tumor cell vaccine in a murine model of renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2514. doi:10.1158/1538-7445.AM2015-2514

Genome-wide analysis of cancer cell-derived Foxp3 target genes in human tongue squamous cell carcinoma cells.

The forkhead transcription factor Foxp3 is essential for differentiation and activation of regulatory T cells (Tregs), and used to be regarded as specific transcription factor of Tregs. In recent years, Foxp3 expression in tumor cells (cancer cell-derived Foxp3) has gained great interest, but its function and molecular mechanisms remain incompletely understood. In the present study, we detected dynamic nuclear translocation of Foxp3 in TSCC cells using immunofluorescent staining. Then we performed a genome-wide analysis of Foxp3 in TSCC cells using a combination of ChIP-on-chip and whole-genome microarray assays. We also compared Foxp3 biding sites in TSCC cells with the known binding sites in human Tregs to show the differences in transcriptional regulation profile. Results indicate that Foxp3 in TSCC cells has distinct biological functions compared with that in Tregs. Cancer cell-derived Foxp3 directly regulates the transcription of genes that affect certain internal biological processes of TSCC cells, and indirectly influences the extracellular microenvironment. This study reveals the relationship between direct and indirect targets genes of Foxp3 in TSCC cells and provide molecular basis of cancer cell-derived Foxp3 function.

FoxP3 Expression in Papillary Thyroid Carcinoma: A Possible Resistance Biomarker to Iodine 131 Treatment

The forkhead transcription factor FoxP3 plays an important role in regulatory T cell (Treg) functions. Tregs are critical in maintaining immunologic tolerance. It has been shown that vaccination against FoxP3-expressing cells is associated with enhancement of tumor immunity. Tregs appear to be increased in blood and in the tumor microenvironment of patients with different cancer types. Tumor cells themselves can express FoxP3. The present study investigates the possible role of FoxP3 expression in a series of human papillary thyroid cancers with a mean follow-up time of 15 years. One hundred five cases of papillary thyroid carcinoma (PTC) were investigated, and FoxP3 expression was evaluated in both tumor cells and tumor-associated infiltrates. For all patients, clinical/pathologic features were considered and the results analyzed by statistical tests. Of the 105 PTC cases, 45 (43%) scored FoxP3-positive and 60 (57%) were negative. FoxP3 staining was localized predominantly in the cytoplasm of tumor cells. In some cases, both nuclear and cytoplasmic staining was seen in infiltrating cells. FoxP3 expression in tumor cells was correlated with the presence of extrathyroid invasion (p=0.04) and distant metastasis (p=0.04), but not with overall survival. Interestingly, FoxP3 expression in neoplastic cells was significantly associated with a resistance phenotype to radioiodine treatment (p=0.041). The data show an association of FoxP3 expression with features of PTC that seem to have a specific impact on radioiodine sensitivity.

FOXP3 expression in tumor cells and implications for cancer progression

FOXP3 is a member of the forkhead/winged-helix family of transcriptional regulators. Defects in the FOXP3 gene cause an X-linked autoimmune/immunodeficiency syndrome in humans and the Scurfy phenotype in mice. FOXP3 acts mainly in regulating the development and function of CD4+CD25+ regulatory T cells. Although initially thought to be specific for these cells, FOXP3 expression has recently been described in non-hematopoietic cells, including epithelial cells of multiple lineages and of different tissue origins. Moreover, FOXP3 expression has been detected in tumor cells of both epithelial and non-epithelial tissues. The role of FOXP3 expression by tumor cells remains controversial, with in vitro studies pointing to an onco-suppressive action, whereas studies conducted on human samples associate FOXP3 expression by tumor cells with metastatic spread. Here, we review evidence for the multi-faceted role of FOXP3 in cancer cells.

335 FOXP3 Expression in Tumor Cells Associated with the Prognosis in Breast Cancer Patients

335 FOXP3 Expression in Tumor Cells Associated with the Prognosis in Breast Cancer Patients

Foxp3 expression in patients with non-small cell lung cancer.

e18059 Background: Lung cancer is rarely cured by the current therapeutic approaches. Although numerous studies have implicated Foxp3 positive T regulatory cells in cancer pathogenesis, the role of Foxp3 in lung cancer pathogenesis remains unknown. Methods: We determined Foxp3 expression, using immunohistochemistry in 44 NSCLC tissue specimens, 20 samples from adjacent non neoplastic lung parenchyma and 5 normal lung tissue specimens. Immunohistochemical reactivity was graded on a scale of 0–3 according to intensity of staining and percentage of immunopositive cells. Foxp3 expression in cancer cells was categorized in three groups (high vs median vs low) using as a cut-off point the 33rd and 66th percentile. The total score for each slide was the sum of the intensity and distribution (between 0 and 6). Statistical analysis was performed with SPSS 17.0. Results: Nuclear Foxp3 immunostaining was detected in al tissues assessed. Foxp3 expression levels were higher in neoplastic cells than in adjacent non neoplastic tissue and normal lung parenchyma. Moreover, Foxp3 expression in tumor cells correlated with lymphocytic Foxp3-immunopositivity and the presence of lymph node metastasis. Furthermore, Foxp3 lymphocytic expression was negatively associated with the age of the patients. Conclusions: Foxp3 is overexpressed in NSCLC cells and tumor infiltrating lymphocytes. Moreover, tumor Foxp3 expression correlates with lymph node metastasis while lymphocytic Foxp3 levels may be age-related.

Nuclear expression of the regulatory T cell marker Foxp3 by non-small cell lung cancer (NSCLC) tumors is positively correlated with histologic grade (95.3)

Abstract Recently, expression of the regulatory T cell associated transcription factor, Foxp3, has been shown in a variety of tumors and tumor cell lines. The function of Foxp3 in tumor cells is currently unknown, but has implications for immune evasion and tumor progression. We have detected the presence of Foxp3 in several tumor cell lines, including 8 NSCLC lines, as well as in fresh tumor and normal adjacent tissue (NAT) samples by flow cytometry and western blot. To examine expression patterns in vivo, immunohistochemistry was performed on paraffin sections obtained from 25 NSCLC adenocarcinomas and 2 NAT. There was no evidence of Foxp3 expression in the normal lung tissues, however, all NSCLC samples included Foxp3+ tumor cells displaying either nuclear and/or cytoplasmic expression. Samples were graded 0-3, indicating no, weak, moderate or strong expression in each compartment. Strong nuclear expression was seen in 8 samples, moderate in 4 and weak in 8. Coefficient correlation analysis revealed a significant correlation (p=0.02) of nuclear expression strength with increasing histologic grade which was regardless of TNM staging. The analysis also suggests a relationship between nuclear Foxp3 expression in tumor cells and in infiltrating lymphocytes. As histologic grade has been reported as an independent prognostic factor for survival in NSCLC, we propose that Foxp3 may be an important element in promoting disease progression by inducing an immunosuppressive microenvironment.

Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy

The Forkhead Box Protein 3 is highly expressed not only in regulatory T cells, but also in tumor cells, acting as a transcriptional repressor of breast oncogenes including HER2. We investigated the prognostic significance of Foxp3 expression in cancer cells in a large cohort of patients with HER2-overexpressing breast carcinoma treated with neoadjuvant chemotherapy. Foxp3-positive tumor cells were detected by immunohistochemistry in 103 patients with primary invasive HER2-overexpressing breast carcinoma, and treated with neoadjuvant chemotherapy, with or without trastuzumab. Kaplan-Meier analysis and Cox regression model were used to assess relapse-free and overall survival, respectively, and according to the presence or the absence of Foxp3 expression in tumor cells. Breast cancer cells were Foxp3+ in 57% of tumors. Foxp3 expression in breast cancer cells was associated with better relapse-free (P = 0.005) and overall survival (P = 0.03). By multivariate analysis, the presence of Foxp3+ tumor cells produced an independent prognostic factor for both better relapse-free (P = 0.006) and overall survival (P = 0.03). These findings indicate that the presence of Foxp3+ tumor cells represents a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma, which could help identify high-risk patients for additional therapies after neoadjuvant chemotherapy.