Intratumoral T cells and survival in epithelial ovarian cancer (2003)

SUMMARY This Italian study aimed to investigate an association between the presence of tumour-infiltrating T cells and clinical outcome in ovarian cancer. Immunohistochemical analysis was performed on 186 frozen specimens from previously untreated patients with FIGO stage III or IV ovarian cancer. Each of the 186 patients underwent debulking surgery and received chemotherapy with platinum, platinum plus cyclophosphamide or platinum plus paclitaxel. Cytosections of the specimen were immunostained with monoclonal antibodies against CD3, CD4, CD8, CD83, CD45, CD45RO, CD19, CD57, CD11c, monokine induced by interferon-g, vascular endothelial growth factor, secondary lymphoid-tissue chemokine (also called exodus-2) and macrophage-derived chemokine. CD3+ T cells were counted manually or by image analysis. CD3+ tumour-infiltrating T cells were detected within tumour-cell islets (intratumoral T cells) in 102 of the 186 tumours (54.8%); they were undetectable in 72 (38.7%); the remaining 12 (6.5%) could not be evaluated. A complete response (CR) to therapy was achieved in 81 of the 186 patients (43.5%); a partial response in 74 patients (39.8%); the remaining 31 patients (16.7%) showed no response. The 5-year progression-free survival (PFS) and overall survival (OS) for all 174 patients whose tumours could be evaluated were 20.9% and 25.3%, respectively. There were significant differences in the distribution of PFS and OS according to the presence or absence of intratumoral T cells (p<0.001 for both comparisons). Patients whose tumours contained T cells had a median PFS of 22.4 months and a median OS of 50.3 months, compared with 5.8 and 18 months, respectively, among patients whose tumours did not contain T cells. The 5-year OS was 38% among 102 patients whose tumours contained T cells but only 4.5% among the 72 patients whose tumours did not. The PFS at 4 years was 31% among patients whose tumours contained T cells and 8.7% among patients whose tumours lacked T cells. Among 174 patients whose tumours could be evaluated for T cell infiltration, 159 were observed for at least 3 years. The absence of intratumoral T cells (in 66 patients) was associated with a 1.5% likelihood of PFS at 3 years and a 7.6% likelihood of OS at 3 years. Among 74 patients with a CR, 61 were observed for at least 3 years. The absence of intratumoral T cells (in 26 patients) was associated with a 3.9% likelihood of PFS at 3 years and a 19.2% likelihood of OS at 3 years. COMMENT Epithelial ovarian carcinoma (EOC) is a common gynaecological malignancy in women.1 About two-thirds of patients present with advanced disease. Debulking surgery followed by platinum-based chemotherapy is the standard approach to treatment; 15%–30% of patients achieve long term survival.2 In most patients failure is primarily due to relapse of the disease, either in the pelvis or in the abdomen or both. A number of prognostic factors have been identified to predict the long term outcome; amount of residual disease after initial debulking surgery and stage at diagnosis are two important clinical factors. Biological prognostic factors that have been studied include DNA ploidy and S-phase fraction,3 morphometry, markers of drug resistance (pGp, c-erbB-2) and tumour spread (cathepsin D, CSF 1), and oncogenes.4,5 The association of improved clinical outcome with the presence of intratumoral T cells has been noted in oesophageal6 and colorectal tumours.7 Tumours of the breast,8 prostate,9 renal cell10 and melanoma11 also display such tumour–host reactions that correlate with clinical outcomes. Tumour-infiltrating T cells have been documented in ovarian cancer12,13 and these tumour-associated lymphocytes recognized tumour antigens.14,15 This study has, for the first time, shown that the presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma. In earlier studies, tumourinfiltrating lymphocytes were successfully isolated from the peritoneal cavities of 50% of patients with EOC and then expanded with low-dose recombinant interleukin-2.16 These findings in the various tumours suggest that intratumoral T cells are a marker of an antitumour response mechanism. Cellular immune