Anke Vanderstraeten

The immune system in the normal endometrium and implications for endometrial cancer development

Although described for the first time some decades ago, the contribution of the immune system to the establishment of tumors has not been extensively pursued for a long time. Over the last decade, however, more and more evidence has been accumulating concerning the role the immune system plays in tumor development and progression and its possible role in patient prognosis. In addition, interest is growing in preclinical and clinical research concerning the use of the immune system in the treatment of cancer. Immunotherapy for gynecological cancers in general, and for endometrial cancer in particular, is still in its infancy. Only a small number of studies, with varying success rates, have been published. Here, we provide a concise overview of the literature available on the role of the immune system in the normal endometrium and in endometrial cancer, in addition to the possible implications for future immunotherapeutic studies.

In Vitro Validation of Survivin as Target Tumor-associated Antigen for Immunotherapy in Uterine Cancer.

Survivin is an antiapoptotic protein, not expressed in terminally differentiated adult tissues, yet overexpressed in several tumors. Therefore, it is an interesting target for immunotherapeutic strategies. In addition to specific overexpression in tumors, tumor survival is mediated by survivin and hence, tumor survival can be tackled by targeting survivin. Survivin expression in uterine cancer was validated by quantitative real-time polymerase chain reaction and immunohistochemistry. In addition, we evaluated survivin immunogenicity by analyzing spontaneous B-cell and T-cell responses in patients. Survivin as a protein was expressed in only a minority of normal tissues, whereas it was being expressed in all of the currently analyzed uterine cancers, both endometrial carcinoma (n=52) and uterine sarcoma (n=52). Survivin RNA transcripts were overexpressed in more aggressive tumors and survivin protein was overexpressed in recurrent endometrial tumors compared with primary tumors. Spontaneous T-cell responses were seen in 10/39 endometrial cancer patients and 3/16 uterine sarcoma patients. In normal controls, T-cell responses were found only in 1 donor (n=21). Although increased antibody titers were found in more aggressive and far-advanced tumors, no differences in B-cell responses were seen. Overall, when compared with normal controls, a B-cell response was only measured in 1/41 uterine sarcoma patients. In conclusion, we currently validated the presence of survivin in uterine cancer. In addition, spontaneous T-cell responses were found in 23.6% of the total patient population. These data indicate that a survivin-specific immune response may be induced spontaneously in patients, further fortifying the eligibility of survivin as an immunotherapeutic target.

Dendritic cell immunotherapy in uterine cancer

Uterine cancer is the most common pelvic gynecological malignancy. Uterine sarcomas and relapsed uterine carcinomas have limited treatment options. The search for new therapies is urgent. Dendritic cell (DC) immunotherapy holds much promise, though has been poorly explored in uterine cancer. This commentary gives an insight in existing DC immunotherapy studies in uterine cancer and summarizes the possibilities and the importance of the loading of tumor antigens onto DC and their subsequent maturation. However, the sole application of DC immunotherapy to target uterine cancer will be insufficient because of tumor-induced immunosuppression, which will hamper the establishment of an effective anti-tumor immune response. The authors give an overview on the limited existing immunosuppressive data and propose a novel approach on DC immunotherapy in uterine cancer.

External validation of non-imaging models for predicting distant metastasis in patients with endometrial cancer

OBJECTIVE To evaluate two non-imaging models designed to predict distant metastasis (stages IIIC-IV) in endometrial carcinoma (EC). Both used preoperative histological and biological findings. One used primary tumoral size, the other did not. METHODS 374 patients operated on for EC by hysterectomy and at least bilateral pelvic lymphadenectomy were included. Patients characteristics, preoperative histological, biological findings and primary tumoral size were used to calculate for each patient two scores (one for each model) for distant metastasis. The accuracy of the models was evaluated in terms of areas under the receiver operating characteristic curves (AUCs), rates of false negatives, and number of patients in the group at low risk to predict stages IIIC-IV. RESULTS 309 and 65 patients had FIGO stages IA-IIIB and IIIC-IV respectively. Thrombocytosis and leukocytosis were not significantly different between patients who had distant metastasis and those who did not. CA125 serum level was significantly higher in patients who had distant metastasis (71.2 vs 32.0U/mL, p<0.001). High-risk preoperative histology and primary tumor diameter >3cm were more frequently observed in patients who had distant metastasis (55.4% and 39.9%, p=0.02 and 21.3% and 8.5%, p=0.003). The AUC were 0.65 [0.63-0.67] and 0.68 [0.63-0.67] with 54% and 93.4% sensitivity, 64% 19.1% specificity. Two hundred and twenty nine patients (61.2%) and 62 (17.0%) were classified as low risk; among them, 30 patients (13.2%) and 4 (6.4%) had final stage IIIC or IV. CONCLUSION Both models turned out to have a low discrimination power in our population. However, the score using primary tumoral size permits to identify a subgroup of patients in whom metastatic probability is low and lymphadenectomy unnecessary. Preoperative CA125 level, histological findings and primary tumoral size remain prognostic factors of stages IIIC-IV and should be included in predictive models.

Evaluation of models to predict lymph node metastasis in endometrial cancer: A multicentre study.

BACKGROUND Several models (preoperative and postoperative) have been developed to predict lymph node metastasis (LNM) in patients with endometrial cancer. The purpose of our investigation was to compare available models in a multicentre study. METHODS In a cohort of 519 patients with endometrial cancer who had undergone primary hysterectomy and at least a pelvic lymphadenectomy, we compared the areas under the receiver-operating characteristic curves (AUCs), calibrations, rates of false negatives (FN), and the number of patients at low-risk for LNM using ten different models (three preoperative and seven postoperative). RESULTS In all, 17.5% of patients among the study population (91 in 519) had LNM. Only one of the three preoperative models and three of the seven postoperative models had an AUC >0.75. Six models were well calibrated. Eight models yielded an FN rate of <5%. Six models could assign more than a third of patients to the low-risk group. One postoperative (a French nomogram) and one preoperative (the Korean Gynecologic Oncology Group [KGOG]) model had an AUC >0.75, to yield an FN rate of <5%, and could assign more than a third of patients to the low-risk group. CONCLUSIONS This study supports the use of the KGOG model to decide upon lymphadenectomy preoperatively in patients with endometrial cancer. For patients who did not have lymphadenectomy, a French nomogram could be applied using pathological characteristics to decide on a secondary lymphadenectomy.

In Vitro Assessment of the Expression and T Cell Immunogenicity of the Tumor-Associated Antigens BORIS, MUC1, hTERT, MAGE-A3 and Sp17 in Uterine Cancer

Background: While immunotherapy moved to the forefront of treatment of various cancers, it remains underexplored for uterine cancer. This might be due to the small patient population with advanced endometrial carcinoma and uterine sarcoma. Data about immunotherapeutic targets are scarce in endometrial carcinoma and lacking in uterine sarcoma. Methods: Expression of five tumor-associated antigens (TAA) (BORIS, MUC1, hTERT, MAGE-A3 and Sp17) was validated in uterine tumor samples by immunohistochemistry (IHC) and/or quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). TAA immunogenicity was analyzed by determining spontaneous T cell responses towards overlapping peptide pools covering the whole TAA in patient blood. Results: At mRNA level, MAGE-A3 and Sp17 were overexpressed in a minority of patients and BORIS was moderately overexpressed (26% in endometrial carcinoma and 62% in uterine sarcoma). hTERT was overexpressed in the vast majority of tumors. On protein level, MUC1 was upregulated in primary, recurrent and metastatic EMCAR and in metastatic US tumors. hTERT protein was highly expressed in both normal and malignant tissue. Spontaneous TAA-specific T cell responses were detected in a minority of patients, except for hTERT to which T cell responses occurred more frequently. Conclusions: These data point to MUC1 and hTERT as most suitable targets based on expression levels and T cell immunogenicity for use in immunotherapeutic regimens.