Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer

doi:10.1073/pnas.0509182102

Intraepithelial CD8⁺ tumor-infiltrating lymphocytes and a high CD8⁺/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer

^*Ludwig Institute for Cancer Research, Memorial Sloan–Kettering Cancer Center, New York, NY 10021; ^‡Department of Epidemiology and Biostatistics, Memorial Sloan–Kettering Cancer Center, and Departments of ^§Cancer Prevention and Population Sciences, ^∥Biostatistics, ^**Gynecologic Oncology, and ^††Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; ^¶College of Human Ecology, Cornell University, Ithaca, NY 14853; ^‡‡Weill Medical College of Cornell University, New York, NY 10021; and ^§§Department of Pathology, Mito Medical Center, National Hospital Organization, Ibaraki 311-3193, Japan

Contributed by Lloyd J. Old, October 27, 2005

Abstract

In a recent report, [Zhang et al. (2003) N. Engl. J. Med. 348, 203–213], the presence of CD3⁺ tumor-infiltrating lymphocytes (TILs) was found to correlate with improved survival in epithelial ovarian cancer. We performed immunohistochemical analysis for TILs and cancer testis antigens in 117 cases of epithelial ovarian cancer. The interrelationship between subpopulations of TILs and expression of cancer testis antigens was investigated, as well as between TILs and overall survival. The median follow-up of the patients was 31 months. Patients with higher frequencies of intraepithelial CD8⁺ T cells demonstrated improved survival compared with patients with lower frequencies [median = 55 versus 26 months; hazard ratio = 0.33; confidence interval (C.I.) = 0.18–0.60; P = 0.0003]. No association was found for CD3⁺ TILs or other subtypes of intraepithelial or stromal TILs. However, the subgroups with high versus low intraepithelial CD8⁺/CD4⁺ TIL ratios had median survival of 74 and 25 months, respectively (hazard ratio = 0.30; C.I. = 0.16–0.55; P = 0.0001). These results indicate that CD4⁺ TILs influence the beneficial effects of CD8⁺ TIL. This unfavorable effect of CD4⁺ T cells on prognosis was found to be due to CD25⁺forkhead box P3 (FOXP3)⁺ regulatory T cells (Treg; suppressor T cells), as indicated by survival of patients with high versus low CD8⁺/Treg ratios (median = 58 versus 23 months; hazard ratio = 0.31; C.I. = 0.17–0.58; P = 0.0002). The favorable prognostic effect of intraepithelial CD8⁺ TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8⁺ TILs and a high CD8⁺/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.

Footnotes

↵ † Present address: Department of Pathology, Tokyo Medical University, 6-1-1 Shinjuku Shinjuku-ku, Tokyo 160-8402, Japan.
↵ ^¶¶To whom correspondence may be addressed. E-mail: lold{at}licr.org. ^∥∥To whom correspondence may be addressed at: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: kunle.odunsi{at}roswellpark.org.
Author contributions: E.S., L.J.O., and K.O. designed research; E.S., H.N., Y.-T.C., F.Q., A.A.J., D.F., S.G., T.O., G.R., K.O., and L.J.O. performed research; S.H.O., J.A., B.B., C.A., J.K., S.L., H.O., E.S., K.O., and L.J.O. analyzed data; and E.S., L.J.O., and K.O. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations: TIL, tumor-infiltrating lymphocyte; CT, cancer testis; Treg, regulatory T cell; EOC, epithelial ovarian cancer; C.I., confidence interval.
Freely available online through the PNAS open access option.