Purpose: To investigate the effect of intraepithelial tumor-infiltrating lymphocytes (ieTIL) and their ligands expressed by cervical tumor cells on the outcome of cervical cancer patients. Experimental Design: The prognostic value of ieTILs was investigated in 115 cases of cervical cancer. T-cell subsets, CD57+ cells, and regulatory T cells (Treg) were enumerated. The associations of these different ieTIL subtypes with human leukocyte antigen (HLA) class I and MHC class I chain-related molecule A (MICA) expression were determined in relation to clinical variables and patient survival. Results: Survival analysis showed that a high number of intraepithelial Treg (FoxP3 + ), a low CD8 + /regulatory T-cell ratio, and a weak HLA-A expression were all associated with worse survival (P = 0.034, 0.025, and 0.033, respectively, log-rank test). Further stratification of patient groups based on HLA-A-MICA expression and HLA-A-MICA-CD8 + /Treg ratio revealed an even poorer survival (P = 0.005). In a multivariate Cox analysis, low CD8 + /Treg ratio (P = 0.047), weak HLA-A-MICA expression (P = 0.003), and weak HLA-A-MICA expression combined with low CD8 + /Treg ratio (P = 0.002) were all found to be independent unfavorable prognostic predictors in cervical carcinoma (hazard ratios, 2.7, 4.0, and 4.9, respectively). Conclusion: Weak HLA-A-MICA expression combined with low CD8 + /Treg ratio reveals a patient group with the poorest survival in cervical cancer. As a single variable, low CD8 + /Treg ratio was a significant independent unfavorable prognostic factor.Cervical cancer is the second most frequent cancer in women worldwide (1). The development of cervical cancer is a multistep process initiated by persistent infection with highrisk human papillomavirus (HPV; ref. 2). After high-risk HPV infection, in a limited number of patients, cervical lesions progress via cervical intraepithelial neoplasia I to cervical intraepithelial neoplasia III to cervical cancer. Cervical carcinoma cells constitutively express the HPV-encoded E6 and E7 oncoproteins. Therefore, peptides derived from these viral antigens can be generated and presented in the context of human leukocyte antigen (HLA) class I to cytotoxic T cells. The presence of substantial numbers of lymphocytes in cervical carcinomas as previously reported by our group and others suggests the presence of a cellular antitumor response (3 -6). Indeed, HPV-specific CD4 + and CD8 + T cells can be isolated from cervical tumors and CD8 + T-cell clones are able to kill cervical cancer cells in vitro (7 -10). However, this does not seem to be sufficient to eradicate the tumor. During tumor development, cancer cells have acquired several strategies to avoid eradication by cytotoxic T cells and natural killer (NK) cells. Among these mechanisms are down-regulation of HLA class I, down-regulation of MHC class I chain-related molecule A (MICA; a cytotoxic T-cell and NK cell ligand), production of immunosuppressive cytokines such as transforming growth factor-h, and the induction of i...

The initiator of coagulation, full-length tissue factor (flTF), in complex with factor VIIa, influences angiogenesis through PAR-2. Recently, an alternatively spliced variant of TF (asTF) was discovered, in which part of the TF extracellular domain, the transmembrane, and cytoplasmic domains are replaced by a unique C terminus. Subcutaneous tumors produced by asTF-secreting cells revealed increased angiogenesis, but it remained unclear if and how angiogenesis is regulated by asTF. Here, we show that asTF enhances angiogenesis in matrigel plugs in mice, whereas a soluble form of flTF only modestly enhances angiogenesis. asTF dose-dependently upregulates angiogenesis ex vivo independent of either PAR-2 or VIIa. Rather, asTF was found to ligate integrins, resulting in downstream signaling. asTF-␣V␤3 integrin interaction induces endothelial cell migration, whereas asTFdependent formation of capillaries in vitro is dependent on ␣6␤1 integrin. Finally, asTF-dependent aortic sprouting is sensitive to ␤1 and ␤3 integrin blockade and a TF-antibody that disrupts asTFintegrin interaction. We conclude that asTF, unlike flTF, does not affect angiogenesis via PAR-dependent pathways but relies on integrin ligation. These findings indicate that asTF may serve as a target to prevent pathological angiogenesis.cancer ͉ coagulation ͉ endothelial cells ͉ integrins

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