Intratumoral T-Cells, Recurrence And Survival In Epithelial Ovarian Cancer
New Engl. J. Med., 348:201-211, 2003
Lin Zhang, M.D.‡
Jose R. Conejo-Garcia, M.D., Ph.D.‡
Dionyssios Katsaros, M.D., Ph.D.‡
Phyllis A. Gimotty, Ph.D.
Marco Massobrio, M.D.
Giorgia Regnani, M.D.
Antonis Makrigiannakis, M.D., Ph.D.
Heidi Gray, M.D.
Katia Schlienger, M.D., Ph.D.
Michael N. Liebman, Ph.D.
Stephen C. Rubin, M.D.
George Coukos, M.D., Ph.D.
‡These authors contributed equally.
From: The Abramson Family Cancer Research Institute, and The Center for Research on Reproduction and Women's Health
Background: Although tumor-infiltrating T-cells have been documented in ovarian carcinoma, a clear effect on clinical outcome has not been established to date.
Methods: We analyzed 186 frozen specimens from advanced stage ovarian carcinoma by immunohistochemistry to assess the distribution of tumor-infiltrating T-cells, and carried out outcome analyses. Molecular analyses were performed in some tumors by real-time PCR.
Results: CD3+ tumor-infiltrating T-cells were detected within tumor cell islets (intratumoral T-cells) in 102/186 tumors (54.8%), while they were undetectable in 72/186 (38.7%) and not evaluable in 12/186 tumors (6.5%). There were significant differences in progression-free survival and overall survival distributions based on the presence or absence of intratumoral T-cells (p<0.0001, both). Five-year overall survival rate was 38% in patients whose tumors had intratumoral T-cells, while it was 4.5% in patients whose tumors had no intratumoral T cells. Significant differences in progression-free survival and overall survival distributions based on the presence or absence of intratumoral T-cells (p<0.0001, both) were also seen among 74 evaluable patients with complete clinical response following debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.8% in patients whose tumors had intratumoral T-cells and 11.9% in patients whose tumors had no intratumoral T cells. Intratumoral T-cells independently predicted delayed recurrence or death by multivariate analysis, and were 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 (VEGF).
Conclusions: Intratumoral T-cells predict improved clinical outcome in advanced ovarian carcinoma.
Patterns of T-cell infiltration in ovarian carcinoma.
| A. |
Double immuno-fluorescent detection of cytokeratin (fluorescein, green) and CD3 Texas red, red) demonstrates the organization of cytokeratin-positive tumor cells in well-defined tumor islets and the presence of CD3+ tumor-infiltrating T lymphocytes both within tumor islets and in peritumoral stroma. |
| B. |
T-cells are in tumor islets as well as in tumor stroma. Note the abundance of intratumoral T-cells. |
| C. |
No intratumoral T-cells are detected. T-cells are restricted exclusively to the peritumoral stroma in this specimen. |
Survival analyses in ovarian carcinoma based on T-cells.
Top: Kaplan-Meier survival curves for progression-free survival (PFS) and overall survival times based on the presence or absence of intratumoral T-cells for 74 evaluable patients with stage III and IV epithelial ovarian cancer and complete response to therapy. The number of patients with events (death or progression), alive under follow-up and alive censored patients are provided at various times under the horizontal axis. (TILs = Intratumoral T cells).
Bottom: Stratified survival curves for residual disease for 74 evaluable consecutive patients with stage III and IV epithelial ovarian cancer and complete response to therapy, based on the presence or absence of intratumoral T-cells. (Optimal debulking: <1 cm residual tumors; suboptimal debulking: =1 cm residual tumors). P-values indicated are for the log-rank statistics used to compare the survival curves.
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