Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer.
OBJECTIVE
To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage serous ovarian cancers.


METHODS
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.
Callahan
Michael J
MJ
Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Nagymanyoki
Zoltan
Z
Bonome
Tomas
T
Johnson
Michael E
ME
Litkouhi
Babak
B
Sullivan
Elizabeth H
EH
Hirsch
Michelle S
MS
Matulonis
Ursula A
UA
Liu
Joyce
J
Birrer
Michael J
MJ
Berkowitz
Ross S
RS
Mok
Samuel C
SC
D018284:Cystadenocarcinoma, Serous / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006681:HLA-D Antigens / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D006681:HLA-D Antigens; C084245:HLA-DM antigens