Expression profiling of ovarian epithelial cancers with intratumoral T cells identifies genes mediating the host immune response: Implications for survival

Abstract

5011 Background: The presence of intratumoral T cells has been demonstrated to be a predictor of increased progression free and overall survival in primary ovarian tumors (Zhang et al. N ENGL J MED 348;3 203–213). Understanding the molecular mechanisms underlying the biology of these tumors may help identify the critical pathway(s) facilitating the host immune response in ovarian cancer. Methods: From 174 primary ovary tumors, a subset of 57 samples with confirmed RNA integrity were randomly selected (35 T cell + / 22 T cell -) and underwent tyramide signal amplification detection on spotted cDNA microarrays (11,000 features). A total of 63 genes with ≥ 2 fold difference in expression were identified using a two group t-test with separate variance (P < .01). The gene list was independently corroborated with a Prediction Analysis of Microarray analysis (P < .01). For validation, quantitative real-time polymerase chain reaction (Q-RT-PCR) was performed on 5 genes identified in the final list. Results: Twelve of 48 genes identified as up-regulated in T cell infiltrated tumors are involved in host immune system response. HLA genes encoding the variable regions of major histocompatibility complexes I and II, as well as beta-2-microglobulin, were elevated in + T cell samples. In addition, complement genes C1r and C3 were up-regulated. Additional genes of interest were also identified in the analysis. Q-RT-PCR results confirmed the microarray expression data. Conclusions: Detection of immune related genes in + T cell samples substantiates the initial observation of a host immune response mounted against altered-self tumor cells. Furthermore, this study suggests a critical role for complement effector genes in the anti-tumor immune response not only as potential T cell chemoattractants, but as direct mediators of tumor cell killing. Besides implicating principal effectors in the cell mediated and innate branches of the immune system, this study has identified genes which may restrict tumor cell proliferation or enhance the host immune response. No significant financial relationships to disclose.