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

Università degli Studi di Torino, Torino, Piedmont, Italy
New England Journal of Medicine (Impact Factor: 55.87). 01/2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177
Source: PubMed


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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Available from: Stephen C Rubin, Oct 22, 2015
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    • "neoadjuvant CRT (Huebner et al, 2012; Agarwal et al, 2013; Fokas et al, 2014), and factors associated with CRT response remain poorly understood. The presence of tumour-infiltrating lymphocytes (TILs) is associated with improved clinical outcome in many cancers (Cho et al, 2003; Zhang et al, 2003; Hiraoka et al, 2006; Loi et al, 2013). In colorectal cancer, the density of tumour-infiltrating T cells is a strong prognostic indicator, even after adjustment for clinical and molecular risk factors (Pages et al, 2005; Galon et al, 2006; Nosho et al, 2010). "
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    ABSTRACT: Background: Foxp3(+) regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown. Methods: Foxp3(+), CD3(+), CD4(+), CD8(+) and IL-17(+) cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated. Results: Stromal Foxp3(+) cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3(+) cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3(+) cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade. Conclusions: Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.British Journal of Cancer advance online publication 8 December 2015. doi:10.1038/bjc.2015.427
    Preview · Article · Dec 2015 · British Journal of Cancer
    • "surgery and current chemotherapeutic regimens are rather ineffective , novel treatment options are of paramount importance (Patel, 2011). Tumour cells are often surrounded by infiltrating inflammatory cells, particularly lymphocytes and macrophages (Smyth et al, 2006) and there is compelling evidence that tumour-infiltrating T-lymphocytes have a favourable effect on patient survival in several malignant tumours, including colorectal (Galon et al, 2006; Mlecnik et al, 2011), ovarian (Zhang et al, 2003), breast (Mahmoud et al, 2011) and pancreatic (Fukunaga et al, 2004) cancer. By investigating a large cohort of BTC, we were able to show a favourable prognostic effect of tumour-infiltrating T-lymphocytes in ECC and GBAC, but not in ICC (Goeppert et al, 2013). "
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    ABSTRACT: Background: Biliary tract cancers (BTC) are rare malignant tumours with a poor prognosis. Previously, we have presented a detailed characterisation of the inflammatory infiltrate in BTC. Here, we analysed the impact of the expression of major histocompatibility complex class I (MHC I) on patient survival and the quantity, as well as the quality of tumour-infiltrating immune cell types in BTC. Methods: MHC I expression was assessed semi-quantitatively in 334 BTC, including extrahepatic (n=129) and intrahepatic cholangiocarcinomas (n=146), as well as adenocarcinomas of the gallbladder (n=59). In addition, 71 high-grade biliary intraepithelial lesions (BilIN 3) were included. Results were correlated with data on antitumour inflammation and investigated with respect to their association with clinicopathological variables and patient survival. Results: BTC showed a wide spectrum of different MHC I expression patterns ranging from complete negativity in some tumours to strong homogenous expression in others. In BilIN 3, significantly higher MHC I expression levels were seen compared to invasive tumours (P=0.004). Patients with strong tumoural MHC I expression had a significantly higher overall survival probability (median survival benefit: 8 months; P=0.006). MHC I expression strongly correlated with the number of tumour-infiltrating T-lymphocytes (CD4(+) and CD8(+)) and macrophages. Conclusions: Differences of MHC I expression predict patient outcome and show correlations with specific components of the inflammatory infiltrate in BTC. These findings contribute to a better understanding of immune response and immune escape phenomena in cholangiocarcinogenesis.British Journal of Cancer advance online publication, 13 October 2015; doi:10.1038/bjc.2015.337
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    • "This failure may partially be attributed to most studies being directed towards the tumour cell-intrinsic events and ignoring the contributory effects of variation in the local immune response. The role of the tumour microenvironment in the survival of tumour cells, and the dual roles of cancer immunoediting via tumour-promoting inflammation and suppression, is becoming well recognised (Zhang et al, 2003; Galon et al, 2006; Schreiber et al, 2011; Baxevanis et al, 2013). There is also increasing awareness that pre-existing adaptive immune status affect response to subsequent therapy across various cancers. "
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    ABSTRACT: Background: Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype. Methods: Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform. Results: A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models. Conclusions: This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.
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