Article

Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer

Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia 19104, USA.
New England Journal of Medicine (Impact Factor: 54.42). 01/2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177
Source: PubMed

ABSTRACT Although tumor-infiltrating T cells have been documented in ovarian carcinoma, a clear association with clinical outcome has not been established.
We performed immunohistochemical analysis of 186 frozen specimens from advanced-stage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction.
CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8 percent); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent among patients whose tumors contained no T cells in islets. Significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons) were also seen among 74 patients with a complete clinical response after debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.9 percent among patients whose tumors contained T cells and 11.9 percent among patients whose tumors contained no T cells in islets. The presence of intratumoral T cells independently correlated with delayed recurrence or delayed death in multivariate analysis and was associated with increased expression of interferon-gamma, interleukin-2, and lymphocyte-attracting chemokines within the tumor. The absence of intratumoral T cells was associated with increased levels of vascular endothelial growth factor.
The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma.

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    • "Cells of the immune system Function Reference CD3+ T lymphocytes The presence of infiltrating lymphocytes is associated with a higher rate Zhang et al., 2003 [25] of survival in patients diagnosed with ovarian cancer Stage III and IV compared with those patients who did not have such lymphocytes; the presence of these lymphocytes is related to a better prognosis of the clinical response ovarian cancer. T CD3+ CD8+ The presence of these lymphocytes is related to a better prognosis for the Helal et al., 2004 [26] lymphocytes clinical response of ovarian cancer. "
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    ABSTRACT: The objective of study was review studies that have investigated the immune response in the presence of a malignant ovarian neoplasia. A review of the literature was performed to identify studies of malignant ovarian neoplasia, particularly studies that addressed the potential for cytokines, nitric oxide, and lymphocytes to mediate an immune response against ovarian cancer. Certain subsets of tumor-infiltrating leukocytes and/or tumor-associated leukocytes have been found to correlate with an improved disease prognosis, while other lymphocyte subsets (such as CD3+/CD4+/CD25+ T cells) have been associated with a poor diagnosis. These data suggest that cytokines can have a protective role, or can promote an immune system defense against a cancer. In particular, certain cytokines (e.g., IL 8, IL 10) represent attractive candidates for the development of new diagnostic, prognostic, and therapeutic strategies for the treatment of ovarian cancer. Keywords: Cytokines, nitric oxide, malignant ovarian neoplasia, cluster of differentiation, lymphocytes.
    European journal of gynaecological oncology 11/2014; 35(5):487-491.
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    • "Malignant progression promotes the selection of less immunogenic tumor variants (Vesely and Schreiber, 2013). However, clinical evidence supports that T cells exert immune pressure against the progression of even advanced cancers (Fridman et al., 2011; Zhang et al., 2003). In addition, de novo elicitation or reactivation of protective immunity is required for the effectiveness of several conventional or targeted anticancer therapies (Zitvogel et al., 2013). "
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    ABSTRACT: Tumor-reactive T cells become unresponsive in advanced tumors. Here we have characterized a common mechanism of T cell unresponsiveness in cancer driven by the upregulation of the transcription factor Forkhead box protein P1 (Foxp1), which prevents CD8(+) T cells from proliferating and upregulating Granzyme-B and interferon-γ in response to tumor antigens. Accordingly, Foxp1-deficient lymphocytes induced rejection of incurable tumors and promoted protection against tumor rechallenge. Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8(+) T cells in response to microenvironmental transforming growth factor-β (TGF-β), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-β-induced c-Jun transcriptional repression, which abrogated T cell activity. Our results unveil a fundamental mechanism of T cell unresponsiveness different from anergy or exhaustion, driven by TGF-β signaling on tumor-associated lymphocytes undergoing Foxp1-dependent transcriptional regulation.
    Immunity 09/2014; 41(3):427-39. DOI:10.1016/j.immuni.2014.08.012
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    • "It has long been established that EOC can stimulate host immune response and that the presence of infiltrating T cells, particularly CD8 + cytotoxic T lymphocytes (CTL), is associated with a better outcome [22] [23] [24] [25] [26]. In accordance with these studies, our results indicate better clinical outcome for the low-volume ascites group, whose tumors are characterized by more abundant tumor infiltrating cells. "
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    ABSTRACT: Epithelial ovarian cancer consists of multiple histotypes differing in etiology and clinical course. The most prevalent histotype is high-grade serous ovarian cancer (HGSOC), which often presents at an advanced stage frequently accompanied with high-volume ascites. While some studies suggest that ascites is associated with poor clinical outcome, most reports have not differentiated between histological subtypes or tumor grade. We compared genome-wide gene expression profiles from a discovery cohort of ten patients diagnosed with stages III-IV HGSOC with high-volume ascites and nine patients with low-volume ascites. An upregulation of immune response genes was detected in tumors from patients presenting with low-volume ascites relative to those with high-volume ascites. Immunohistochemical studies performed on tissue microarrays confirmed higher expression of proteins encoded by immune response genes and increased tumorinfiltrating cells in tumors associated with low-volume ascites. Comparison of 149 advanced-stage HGSOC cases with differential ascites volume at time of primary surgery indicated low-volume ascites correlated with better surgical outcome and longer overall survival. These findings suggest that advanced stage HGSOC presenting with low-volume ascites reflects a unique subgroup of HGSOC, which is associated with upregulation of immune related genes, more abundant tumor infiltrating cells and better clinical outcomes.
    BioMed Research International 05/2014; 2014:367103. DOI:10.1155/2014/367103
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