Showing papers by "Wolf H. Fridman published in 2009"

ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks

Abstract: We have developed ClueGO, an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways and creates a functionally organized GO/pathway term network. It can analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms. A one-click update option allows ClueGO to automatically download the most recent GO/KEGG release at any time. ClueGO provides an intuitive representation of the analysis results and can be optionally used in conjunction with the GOlorize plug-in.

In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer

Abstract: Purpose Many patients who present with early-stage colorectal cancer (International Union Against Cancer TNM stages I and II) are nevertheless at high risk of relapse. We hypothesized that intratumoral immune reaction could influence their prognosis. Patients and Methods The intratumoral immune reaction was investigated in 29 tumors by large-scale real-time polymerase chain reaction. Cytotoxic (CD8) and memory (CD45RO) T cells were quantified by immunohistochemical analyses of tissue microarrays from the center (CT) and the invasive margin (IM) of the 602 tumors from two independent cohorts. The results were correlated with tumor recurrence and patient survival. Results Patients with a strong infiltration of CD45RO+ cells in the tumor exhibited an increased expression of T-helper 1 and cytotoxicity-related genes. Densities of CD45RO+ and CD8+ cells in tumor regions (CT/IM) classified the patients into four distinct prognostic groups based on the presence of high density of each marker in each tumor region...

Coordination of intratumoral immune reaction and human colorectal cancer recurrence.

Abstract: A role for the immune system in controlling the progression of solid tumors has been established in several mouse models. However, the effect of immune responses and tumor escape on patient prognosis in the context of human cancer is poorly understood. Here, we investigate the cellular and molecular parameters that could describe in situ immune responses in human colorectal cancer according to clinical parameters of metastatic lymph node or distant organ invasion (META- or META+ patients). Primary tumor samples of colorectal carcinoma were analyzed by integrating large-scale phenotypic (flow cytometry, 39 patients) and gene expression (real time reverse transcription-PCR, 103 patients) data sets related to immune and protumoral processes. In META- colorectal cancer primary tumors with high densities of T cells, we observed significant positive correlations between markers of innate immune cells [tumor-associated macrophages, dendritic cells, natural killer (NK) cells, and NKT cells] and markers of early-activated T cells. Significant correlations were also observed between markers of cytotoxic and effector memory T-cell subpopulations. These correlation profiles were absent in tumors with low T-cell infiltrates and were altered in META+ tumors with high T-cell infiltrates. We show that the coexpression of genes mediating cytotoxicity (GNLY) and Th1 adaptive immune responses (IRF1) accurately predicted patient survival independently of the metastatic status. High intratumoral mRNA expression of the proangiogenic mediator vascular endothelial growth factor was associated with significantly reduced survival rates in patients expressing high mRNA levels of GNLY. Investigation of the colorectal cancer primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response.

The high frequency of Complement Factor H-Related CFHR1 Gene Deletion is restricted to specific subgroups of patients with atypical Haemolytic Uraemic Syndrome

Abstract: Background: Deletion of the Complement Factor H Related 1 (CFHR1) gene is a consequence of non-allelic homologous recombination and has been reported to be more frequent in atypical haemolytic uraemic syndrome (aHUS) patients than in the normal population. Therefore, it is considered a susceptibility factor for the disease. Atypical HUS is associated with hereditary or acquired abnormalities that lead to uncontrolled alternative pathway complement activation. We tested the CFHR1 deletion for association with aHUS in a population of French aHUS cases and controls. Furthermore, we examined the effect of the deletion in the context of known aHUS risk factors. Methodology and findings: 177 aHUS patients and 70 healthy donors were studied. The number of CFHR1 alleles was quantified by Multiplex Ligation-dependant Probe Amplification (MLPA). The frequency of the deleted allele was significantly higher in aHUS patients than in controls (22.7% versus 8.2%, P<0.001). The highest frequency was in the subgroup of patients exhibiting anti-Factor H (FH) auto-antibodies (92.9%, P<0.0001 versus controls) and in the group of patients exhibiting a Factor I (CFI) gene mutation (31.8%, P<0.001 versus controls). The CFHR1 deletion was not significantly more frequent in the cohort of aHUS patients when patients with anti-FH IgG or CFI mutation were excluded. Conclusions: The high frequency of CFHR1 deletion in aHUS patients is restricted to the subgroups of patients presenting with anti-FH auto-antibodies or, to a lesser degree, CFI mutation. These results suggest that the CFHR1 deletion plays a secondary role in susceptibility to aHUS.

Revisiting the prognostic value of regulatory T cells in patients with cancer.

Abstract: TO THE EDITOR: In a recent issue of Journal of Clinical Oncology, Salama et al reported better survival associated with a high density of intratumoral FOXP3 regulatory T cells (Tregs) in colorectal cancer. In their discussion, the authors stated that these results were unexpected, surprising, and in marked contrast to the poor prognostic value of Treg presence in other tumors. However, it must be emphasized that these results are in line with the preclinical studies of Erdman et al performed in apc mice, in which the tumor suppressor gene apc was inactivated, leading to formation of intestinal adenomas and recapitulating early events in human colorectal cancer. Adoptive transfer of Tregs into these mice resulted in prevention of intestinal adenomas and regression of established tumors. In another mouse model of bacteria-driven inflammation and cancer in the lower bowel, administration of Tregs also inhibited microbially induced inflammation and development of cancer. In patients with follicular lymphoma and Hodgkin’s lymphoma, it is now well established that high number of intratumoral Tregs is associated with longer disease-free and overall survival, even in multivariate analyses. This correlation between the number of Tregs and favorable clinical outcome has also recently been extended in some solid tumors. In patients with head and neck cancer, we found that tumor infiltration by FOXP3 CD4 Tregs was positively associated with better locoregional control of the tumor. In our study, multivariate analysis showed that the only significant prognostic factors related to locoregional control were T stage and Treg infiltration of the tumor. Frequency of FOXP3 CD4 Tregs has also been shown to be higher in patients with no evidence of disease after oncologic therapy than in patients with active disease. Various parameters may explain these seemingly contradictory results regarding prognostic value of Tregs in patients with cancer. First, the role of Tregs seems to differ according to tumor stage. For example, patients with early-stage (stage I) non–small-cell lung carcinoma and a high proportion of Tregs relative to tumor-infiltrating lymphocytes had a significantly high risk of recurrence. In the whole population of patients with ovarian cancer, Tregs were associated with poor prognosis, whereas in patients with advanced or metastatic disease, absolute number of FOXP3 lymphocytes infiltrating tumor epithelium was an independent factor for longer disease-specific survival. These data are supported by a preclinical study in mice, in which Tregs often served as the dominant immune escape mechanism early in tumor progression; the elimination of these cells before tumor challenge resulted in tumor-free survival in most mice, whereas their depletion in mice with established tumors had no therapeutic effect. Second, because it is supposed that the deleterious effect of Tregs is mediated by their inhibitory activity on antitumor effector cells, it is not surprising that various studies have reported that the ratio of CD8 T cells to Tregs had more impact on patient survival that the number of Tregs or intraepithelial CD8 T cells alone. Focusing only on Tregs—without knowledge of the balance between Tregs and effector cells—may lead to some bias in data interpretation. Third, unlike in mice, FOXP3 expression, which has been used in studies by Salama et al and others to define Tregs, is not confined to certain populations in humans. It has been shown that activated CD4 CD25 effector T cells transiently express FOXP3 with or without acquisition of suppressive functions. Subsets of CD8 T cells as well as tumor cells might also express FOXP3. Therefore, although FOXP3 is currently the best marker available for immunohistochemical staining to characterize Tregs, the simple use of this marker may overestimate this Treg population. Depending on the study and proportion of FOXP3 -activated CD4 T cells or CD8 T cells in tissue specimens, the simple enumeration of FOXP3 -positive cells without functional analysis will not correspond to the same levels of Tregs in the various samples and thus may lead to bias in interpretation of data. With respect to mechanisms underlying the favorable role of Tregs in tumor control, two hypotheses could be proposed. Hematologic malignancies and solid tumors (head and neck cancer and colon cancer), in which presence of Tregs correlates with good clinical outcome, are tumors heavily infiltrated by inflammatory innate immune cells (ie, macrophages and neutrophils), producing inflammatory cytokines, growth factors, and pro-angiogenic molecules favoring tumor progression. In mice, Tregs have the ability to suppress inflammation triggered by innate immune cells. In humans, FasL Tregs may kill monocytes and macrophages and then decrease their protumor effect during cancer development. In addition, it has been well documented that Tregs may express cytotoxic molecules such as granzyme and perforin and induce cell death of normal cells such as B cells. It has been demonstrated that adoptive immunotherapy with CD4 CD25 Tregs can also decrease tumor multiplicity through rapid induction of apoptosis of intestinal tumors, which supports the possibility of Tregs directly or indirectly inducing tumor apoptosis. We feel that our comments will help to better highlight the work of Salama et al. Finally, we hope our comments show that the data presented by Salama et al were original, but not so unexpected.