Immune biomarkers in ovarian cancer
Emerging evidence over the past decade has revealed the significance of tumor-host interactions and of the tumor microenvironment in tumor growth and progression. Among these mechanisms, a bulk of experimental evidence in animal tumor models has clearly established that the ability of the host to recognize and attack tumors, or vice versa the ability of tumors to evade such a response, largely determines the fate of developing tumors.1 It is now generally accepted that human tumors may be antigenic, i.e. cancer cells express unique tumor-specific antigens that, in select patients, may be recognized by the immune system. Lessons learned from melanoma indicate that such antigens may be tumor-specific proteins that are normally absent in adult normal tissues except for germline cells, tissue-specific differentiation proteins that are normally not expressed within a specific organ, mutated proteins, overexpressed proteins, or unmasked protein epitopes due to protein underglycosylation. Strong proof that spontaneously occurring tumor-reactive T cells are directed against tumor antigens and can reject tumors in the human comes from recent adoptive T-cell therapy in melanoma. Ex vivo expanded T-cell clones induced tumor regression under conditions enhancing T-cell homeostasis. A significant association has been demonstrated between tumor regression and the persistence of adoptively transferred T-cell clones in peripheral blood.2-4 In epithelial ovarian carcinoma, antigen characterization has not been systematic, but evidence exists that tumor-associated antigens are present. The best differentiation tumor rejection antigen identified to date is the HLA-A2-restricted onconeuronal protein cdr2, shared by ovarian cancer cells and cerebellar Purkinje cells. Its recognition by cytotoxic lymphocytes (CTL) is associated with paraneoplastic cerebellar degeneration and occult ovarian cancer.5 Other antigens identified in ovarian cancer include the following: HER2 protein, the product of the ERBB2 oncogene; the TP53 tumor suppressor gene protein product p53; topoisomerase-IIa; folate-binding protein; amino enhancer of split protein; sialylated TN (sTN), a mucin antigen; MUC-1; NY-ESO-1, a testis differentiation antigen; and mesothelin (for reviews see reference 6). In addition, universal tumor antigens such as human telomerase reverse transcriptase (hTERT), cytochrome P450 CYP1B1, and surviving7 are expressed by epithelial ovarian carcinoma cells.8,9 Tumorspecific T cells secreting interferon-γ (IFN-γ) have been reported in the peripheral blood of patients with advanced-stage ovarian carcinoma, indicating that tumor antigens are in fact recognized spontaneously in vivo.10.