Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer.
BACKGROUND
Tumour-infiltrating lymphocytes (TILs) are predictors of disease-specific survival (DSS) in ovarian cancer. It is largely unknown what factors contribute to lymphocyte recruitment. Our aim was to evaluate genes and pathways contributing to infiltration of cytotoxic T lymphocytes (CTLs) in advanced-stage serous ovarian cancer.


METHODS
For this study global gene expression was compared between low TIL (n=25) and high TIL tumours (n=24). The differences in gene expression were evaluated using parametric T-testing. Selectively enriched biological pathways were identified with gene set enrichment analysis. Prognostic influence was validated in 157 late-stage serous ovarian cancer patients. Using immunohistochemistry, association of selected genes from identified pathways with CTL was validated.


RESULTS
The presence of CTL was associated with 320 genes and 23 pathways (P<0.05). In addition, 54 genes and 8 pathways were also associated with DSS in our validation cohort. Immunohistochemical evaluation showed strong correlations between MHC class I and II membrane expression, parts of the antigen processing and presentation pathway, and CTL recruitment.


CONCLUSIONS
Gene expression profiling and pathway analyses are valuable tools to obtain more understanding of tumour characteristics influencing lymphocyte recruitment in advanced-stage serous ovarian cancer. Identified genes and pathways need to be further investigated for suitability as therapeutic targets.
Leffers
N
N
Department of Gynaecologic Oncology (CB22), University Medical Center Groningen, University of Groningen, PO Box 30.001, Groningen 9700 RB, The Netherlands.
Fehrmann
R S N
RS
Gooden
M J M
MJ
Schulze
U R J
UR
Ten Hoor
K A
KA
Hollema
H
H
Boezen
H M
HM
Daemen
T
T
de Jong
S
S
Nijman
H W
HW
van der Zee
A G J
AG
D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000191:economics* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology*; D011379:Prognosis; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D006680:HLA Antigens