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. 2008 Dec 1;14(23):7667-73.
doi: 10.1158/1078-0432.CCR-08-0479.

Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer

Michael J Callahan  1 , Zoltan Nagymanyoki, Tomas Bonome, Michael E Johnson, Babak Litkouhi, Elizabeth H Sullivan, Michelle S Hirsch, Ursula A Matulonis, Joyce Liu, Michael J Birrer, Ross S Berkowitz, Samuel C Mok
Affiliations

Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer

Michael J Callahan et al. Clin Cancer Res. .

Abstract

Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage serous ovarian cancers.

Experimental design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes. Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival analyses were done combining CD8 T lymphocyte number and HLA-DMB expression with standard prognostic factors.

Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement in median overall survival in both univariate and multivariate analyses.

Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are associated with improved survival in advanced-stage serous ovarian cancer.

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Figures

Figure 1
Figure 1
1a: High-Grade, Advanced-Stage Serous Ovarian Cancer Immunohistochemically Stained for CD8 T Lymphocytes and HLA-DMB. Marked CD8 T lymphocyte (red) infiltration in the tumor epithelium (10X) 1b: Scant CD8 T lymphocyte infiltration in the tumor epithelium (10X) 1c: High expression of HLA-DMB (red) in the tumor cell cytoplasm(10X) 1d: Low expression of HLA-DMB (10X)
Figure 2
Figure 2
2a: Kaplan-Meier Survival Analysis. Marked CD8 T lymphocyte infiltration in the tumor epithelium (median overall survival, 50.0 months) versus scant CD8 T lymphocyte infiltration in the tumor epithelium (median overall survival, 30.0 months), p=0.021. Cut-off for marked infiltration of CD8 T lymphocytes was the 75th percentile. 2b: High expression of HLA-DMB in the tumor epithelium (median overall survival, 59.0 months) versus low expression of HLA-DMB in the tumor epithelium (median overall survival, 27.0 months), p=0.003. Cut-off for high expression of HLA-DMB was the 33rd percentile.
Figure 3
Figure 3
RMA Normalization, Pearson correlation p<0.01, increasing tumor-infiltrating CD8 T lymphocyte number (left to right), genes ordered according to descending correlation coefficient.
Figure 4
Figure 4
4a: High-Grade, Advanced-Stage Serous Ovarian Cancer, Double-Immunofluorescence Staining for CD8 T Lymphocytes and HLA-DR. CD8 T lymphocytes (red) infiltrating the tumor epithelium. (20X) 4b: HLA-DR localized to the tumor cell membrane. (20X) 4c: Tumor cell nuclei marked with DAPI (blue). (20X) 4d: HLA-DR positive CD8 T lymphocytes (orange) indicating activated status. (20X)
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