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Abstract Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

Genomic instability is a driver and accelerator of tumorigenesis and influences disease outcomes across cancer types. Although genomic instability has been associated with immune evasion and worsened disease prognosis, emerging evidence shows that genomic instability instigates pro-inflammatory signaling and enhances the immunogenicity of tumor cells, making them more susceptible to immune recognition. While this paradoxical role of genomic instability in cancer is complex and likely context-dependent, understanding it is essential for improving the success rates of cancer immunotherapy. In this review, we provide an overview of the underlying mechanisms that link genomic instability to pro-inflammatory signaling and increased immune surveillance in the context of cancer, as well as discuss how genomically unstable tumors evade the immune system. A better understanding of the molecular crosstalk between genomic instability, inflammatory signaling, and immune surveillance could guide the exploitation of immunotherapeutic vulnerabilities in cancer.

Abstract Objectives Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. Methods Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. Results Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. Conclusions [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. Critical relevance statement Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. Key points • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach. Graphical Abstract

Abstract Background Immune checkpoint inhibitors (ICIs) have made significant progress in oncotherapy improving survival of patients. However, the benefits are limited to only a small subgroup of patients who could achieve durable responses. Early prediction of response may enable treatment optimization and patient stratification. Therefore, developing appropriate biomarkers is critical to monitoring efficacy and assessing patient response to ICIs. Main body Herein, we first introduce a new potential biomarker, CD103, expressed on tissue-resident memory T cells, and discuss the potential application of CD103 PET imaging in predicting immune checkpoint inhibitor treatment. In addition, we describe the current targets of ImmunoPET and compare these targets with CD103. To assess the benefit of PET imaging, a comparative analysis between ImmunoPET and other imaging techniques commonly employed for tumor diagnosis was performed. Additionally, we compare ImmunoPET and immunohistochemistry (IHC), a widely utilized clinical method for biomarker identification with respect to visualizing the immune targets. Conclusion CD103 ImmunoPET is a promising method for determining tumor-infiltrating lymphocytes (TILs) load and response to ICIs, thereby addressing the lack of reliable biomarkers in cancer immunotherapy. Compared to general T cell markers, CD103 is a specific marker for tissue-resident memory T cells, which number increases during successful ICI therapy. ImmunoPET offers noninvasive, dynamic imaging of specific markers, complemented by detailed molecular information from immunohistochemistry (IHC). Radiomics can extract quantitative features from traditional imaging methods, while near-infrared fluorescence (NIRF) imaging aids tumor detection during surgery. In the era of precision medicine, combining such methods will offer a more comprehensive approach to cancer diagnosis and treatment.

Abstract Background CD103 is an integrin specifically expressed on the surface of cancer-reactive T cells. The number of CD103+ T cells significantly increases during successful immunotherapy and might therefore be an attractive biomarker for noninvasive PET imaging of immunotherapy response. Since the long half-life of antibodies preclude repeat imaging of CD103+ T cell dynamics early in therapy, we therefore here explored PET imaging with CD103 Fab fragments radiolabeled with a longer (89Zr) and shorter-lived radionuclide (68Ga). Methods Antihuman CD103 Fab fragment Fab01A was radiolabeled with 89Zr or 68Ga, generating [89Zr]Zr-hCD103.Fab01A and [68Ga]Ga-hCD103.Fab01A, respectively. In vivo evaluation of these tracers was performed in male nude mice (BALB/cOlaHsd-Foxn1nu) with established CD103-expressing CHO (CHO.CD103) or CHO-wildtype (CHO.K1) xenografts, followed by serial PET imaging and ex vivo bio-distribution. Results [89Zr]Zr-hCD103.Fab01A showed high tracer uptake in CD103+ xenografts as early as 3 h post-injection. However, the background signal remained high in the 3- and 6-h scans. The background was relatively low at 24 h after injection with sufficient tumor uptake. [68Ga]Ga-hCD103.Fab01Ashowed acceptable uptake and signal-to-noise ratio in CD103+ xenografts after 3 h, which decreased at subsequent time points. Conclusion [89Zr]Zr-hCD103.Fab01A demonstrated a relatively low background and high xenograft uptake in scans as early as 6 h post-injection and could be explored for repeat imaging during immunotherapy in clinical trials. 18F or 64Cu could be explored as alternative to 68Ga in optimizing half-life and radiation burden of the tracer.

Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.

Abstract Background A frozen section diagnosis of a borderline ovarian tumor with suspicious features of invasive carcinoma (“at least borderline” or synonymous descriptions) presents us with the dilemma of whether or not to perform a full ovarian cancer staging procedure. Quantification of this dilemma may help us with the issue of this clinical decision. The present study assessed and compared both the prevalence of straightforward borderline and “at least borderline” frozen section diagnoses and the proportion of these women with a final histopathological diagnosis of invasive carcinoma, with a special interest in histologic subtypes. Methods A retrospective cohort study was performed in three hospitals in The Netherlands. All women that underwent ovarian surgery with perioperative frozen section evaluation in one of these hospitals between January 2007 and July 2018 were identified and included in case of a borderline or “at least borderline” frozen section diagnosis and a borderline ovarian tumor or invasive carcinoma as a final diagnosis. Results A total of 223 women were included, of which 41 women (18.4%) were diagnosed with “at least borderline” at frozen section. Thirteen of forty-one women (31.7%) following “at least borderline” frozen section diagnosis and 14 of 182 women (7.7%) following a straightforward borderline frozen section diagnosis were diagnosed with invasive carcinoma at paraffin section evaluation (p

Purpose CD103, an integrin specifically expressed on the surface of cancer-reactive T cells, is significantly increased during successful immunotherapy across human malignancies. In this study, we describe the generation and zirconium-89 (89Zr) radiolabeling of monoclonal antibody (mAb) clones that specifically recognize human CD103 for non-invasive immune positron-emission tomography (PET) imaging of T cell infiltration as potential biomarker for effective anticancer immune responses.Experimental design First, to determine the feasibility of anti-CD103 immuno-PET to visualize CD103-positive cells at physiologically and clinically relevant target densities, we developed an 89Zr-anti-murine CD103 PET tracer. Healthy, non-tumor bearing C57BL/6 mice underwent serial PET imaging after intravenous injection, followed by ex vivo biodistribution. Tracer specificity and macroscopic tissue distribution were studied using autoradiography combined with CD103 immunohistochemistry. Next, we generated and screened six unique mAbs that specifically target human CD103 positive cells. Optimal candidates were selected for 89Zr-anti-human CD103 PET development. Nude mice (BALB/cOlaHsd-Foxn1nu) with established CD103 expressing Chinese hamster ovary (CHO) or CHO wild-type xenografts were injected with 89Zr-anti-human CD103 mAbs and underwent serial PET imaging, followed by ex vivo biodistribution.Results 89Zr-anti-murine CD103 PET imaging identified CD103-positive tissues at clinically relevant target densities. For human anti-human CD103 PET development two clones were selected based on strong binding to the CD103+ CD8+ T cell subpopulation in ovarian cancer tumor digests, non-overlapping binding epitopes and differential CD103 blocking properties. In vivo, both 89Zr-anti-human CD103 tracers showed high target-to-background ratios, high target site selectivity and a high sensitivity in human CD103 positive xenografts.Conclusion CD103 immuno-PET tracers visualize CD103 T cells at relevant densities and are suitable for future non-invasive assessment of cancer reactive T cell infiltration.

Reactivation of tumor infiltrating T lymphocytes (TILs) with immune checkpoint inhibitors or co-stimulators has proven to be an effective anti-cancer strategy for a broad range of malignancies. However, epithelial ovarian cancer (EOC) remains largely refractory to current T cell-targeting immunotherapeutics. Therefore, identification of novel immune checkpoint targets and biomarkers with prognostic value for EOC is warranted. Combining multicolor immunofluorescent staining’s with single cell RNA-sequencing analysis, we here identified a TIM-3/CXCL13-positive tissue-resident memory (CD8/CD103-positive) T cell (Trm) population in EOC. Analysis of a cohort of ~175 patients with high-grade serous EOC revealed TIM-3-positive Trm were significantly associated with improved patient survival. As CXCL13-positive CD8-positive T cells have been strongly linked to patient response to anti-PD1 immune checkpoint blockade, combinatorial TIM-3 and PD-1 blockade therapy may be of interest for the (re)activation of anti-cancer immunity in EOC.

Objectives: Discordance between frozen section diagnosis and the definite histopathological diagnosis and the fact that the frozen section result is not always unambiguous, may contribute to differences in clinical practice regarding perioperative treatment and follow-up of borderline ovarian tumours (BOTs) patients amongst gynaecologic oncologists, which may lead to over- and undertreatment. The aim of the study was to map the Dutch gynaecologists' preferred treatment and follow-up strategy in case of BOTs. Methods: A questionnaire was sent to all Dutch gynaecologists involved in ovarian surgery with perioperative frozen section analysis, and the outcomes were assessed using descriptive statistics. Results: Nearly half of the respondents (41.0%) would not perform a staging procedure in case of a BOT. In case of an ambiguous frozen section diagnosis, tending towards invasive carcinoma, a considerable number (sBOT 56.4%; mBOT 30.8%) would perform a lymph node sampling as part of the staging procedure. A relaparotomy/relaparoscopy, to perform a lymph node sampling in case of a serous or mucinous carcinoma after a BOT frozen section diagnosis, would be performed by 97.4% and 48.7% of the respondents, respectively. Conclusions: A considerable number of gynaecologists would perform a staging procedure that is recommended for ovarian cancer in case of an ambiguous BOT frozen section diagnosis, especially for serous tumours. In addition, nearly all gynaecologists would perform a second procedure including a lymph node sampling in case of a serous invasive carcinoma after a BOT frozen section diagnosis, which applies to half of the gynaecologists in case of a mucinous carcinoma. Keywords: Borderline tumours of the ovary, Staging procedure, Frozen section analysis, Questionnaire, Gynaecologic oncologist, Semi-specialized gynaecologists

Activation of STimulator of INterferon Genes (STING) is important for induction of anti-tumor immunity. A dysfunctional STING pathway is observed in multiple cancer types and associates with poor prognosis and inferior response to immunotherapy. However, the association between STING and prognosis in virally induced cancers such as HPV-positive cervical cancer remains unknown. Here, we investigated the prognostic value of STING protein levels in cervical cancer using tumor tissue microarrays of two patient groups, primarily treated with surgery (n = 251) or radio(chemo)therapy (n = 255). We also studied CD103, an integrin that marks tumor-reactive cytotoxic T cells that reside in tumor epithelium and that is reported to associate with improved prognosis. Notably, we found that a high level of STING protein was an independent prognostic factor for improved survival in both the surgery and radio(chemo)therapy group. High infiltration of CD103+ T cells was associated with improved survival in the radio(chemo)therapy group. The combination of STING levels and CD103+ T cell infiltration is strongly associated with improved prognosis. We conclude that combining the prognostic values of STING and CD103 may improve the risk stratification of cervical cancer patients, independent from established clinical prognostic parameters.

Epithelial Ovarian cancer (EOC) is the most lethal gynecological malignancy and has limited curative therapeutic options. Immunotherapy for EOC is promising, but clinical efficacy remains restricted to a small percentage of patients. Several lines of evidence suggest that the low response rate might be improved by combining immunotherapy with carboplatin and paclitaxel, the standard-of-care chemotherapy for EOC. Here, we assessed the immune contexture of EOC tumors, draining lymph nodes, and peripheral blood mononuclear cells during carboplatin/paclitaxel chemotherapy. We observed that the immune contexture of EOC patients is defined by the tissue of origin, independent of exposure to chemotherapy. Summarized, draining lymph nodes were characterized by a quiescent microenvironment composed of mostly non-proliferating naïve CD4 + T cells. Circulating T cells shared phenotypic features of both lymph nodes and tumor-infiltrating immune cells. Immunologically ‘hot’ ovarian tumors were characterized by ICOS, GITR, and PD-1 expression on CD4 + and CD8 + cells, independent of chemotherapy. The presence of PD-1 + cells in tumors prior to, but not after, chemotherapy was associated with disease-specific survival (DSS). Accordingly, we observed high MHC-I expression in tumors prior to chemotherapy, but minimal MHC-I expression in tumors after neoadjuvant chemotherapy, even though there were no differences in the number of tumor-infiltrating lymphocytes (TIL) in both groups. We therefore speculate that the TIL influx into the chemotherapy tumor microenvironment may be a consequence of the general inflammatory nature of chemotherapy-experienced tumors. Strategies to upregulate MHC-I during or after neoadjuvant chemotherapy may thus improve treatment outcome in these patients.

Abstract Background Implementation of human papillomavirus (HPV) vaccination raised concerns that vaccination could lead to riskier sexual behavior. This study explored how possible differences in sexual behavior and HPV knowledge developed over time between HPV-vaccinated and unvaccinated girls. Methods A random sample of 19,939 girls (16–17 year olds) eligible for the catch-up HPV vaccination campaign in the Netherlands was invited for a longitudinal study with questionnaires every 6 months over a two-year follow-up period. Possible differences over time between vaccinated and unvaccinated participants were studied using generalized equations estimation (GEE). Results A total of 2989 girls participated in round one, of which 1574 participated (52.7%) in the final 5th round. Vaccinated girls were more likely to live in more urban areas (OR 1.28, 95%CI 1.10–1.47) and to use alcohol (OR 1.46, 95%CI 1.24–1.70) and contraceptives (OR 1.69, 95%CI 1.45–1.97). Vaccinated and unvaccinated girls showed comparable knowledge on HPV, HPV vaccination, and transmission. Vaccinated girls were more likely to be sexually active (OR 1.19, 95%CI 1.02–1.39), and this difference increased over time (OR for interaction 1.06, 95%CI 1.00–1.12). However, they had a slightly lower number of lifetime sexual partners (mean difference − 0.20, 95%CI -0.41-0.00). Vaccinated girls were less likely to use a condom with a steady partner (aOR 0.71, 95%CI 0.56–0.89). However, the difference between vaccinated and unvaccinated girls with regard to condom use with casual or steady partner(s) did not significantly change over time. Conclusion Overall, we did not find indications that vaccination influenced sexual behavior in girls during 2 years of follow-up. The few differences found may be related to existing disparities in the socio-demographic characteristics of the young population pointing to the importance and improvement of education with regard to safe sex practices. Our findings do not suggest that vaccination status is associated with changes in sexual risk behavior and thus it is unlikely that this might influence the effectiveness of the vaccination program.

Cervical cancer develops as a result of infection with high-risk human papillomavirus (HPV) through persistent expression of early proteins E6 and E7. Our group pioneered a recombinant viral vector system based on Semliki Forest virus (SFV) for vaccination against cervical cancer. The most striking benefit of this alphavirus vector-based vaccine platform is its high potency. DNA vaccines on the other hand, have a major advantage with respect to ease of production. In this study, the benefits associated with both SFV-based vaccines and DNA vaccines were combined with the development of a DNA-launched RNA replicon (DREP) vaccine targeting cervical cancer. Using intradermal delivery followed by electroporation, we demonstrated that DREP encoding for E6,7 (DREP-E6,7) induced effective, therapeutic antitumor immunity. While immunizations with a conventional DNA vaccine did not prevent tumor outgrowth, immunization with a 200-fold lower equimolar dose of DREP (0.05 µg of DREP) resulted in approximately 85% of tumor-free mice. To overcome the safety concern of potential malignant transformation at the vaccination site, we evaluated the anti-tumor effect of a DREP vaccine encoding a shuffled version of E7 (DREP-E7sh). DREP-E7sh delayed tumor growth yet not to the same extent as DREP-E6,7. In addition, inclusion of a helper cassette and an ER targeting signal (sigHelp) did not significantly further enhance the suppression of tumor outgrowth in the long term, albeit exhibiting better tumor control early after immunization. Collectively, this study points towards the clinical evaluation of DREP encoding HPV antigens as a potent immunotherapy for patients with HPV16 (pre)-malignancies.

Tumor vaccine design requires prediction and validation of immunogenic MHC class I epitopes expressed by target cells as well as MHC class II epitopes expressed by antigen-presenting cells essential for the induction of optimal immune responses. Epitope prediction methods are based on different algorithms and are instrumental for a first screening of possible epitopes. However, their results do not reflect a one-to-one correlation with experimental data. We combined several in silico prediction methods to unravel the most promising C57BL/6 mouse-restricted Hepatitis C virus (HCV) MHC class I epitopes and validated these epitopes in vitro and in vivo. Cytotoxic T lymphocyte (CTL) epitopes within the HCV non-structural proteins were identified, and proteasomal cleavage sites and helper T cell (Th) epitopes at close proximity to these CTL epitopes were analyzed using multiple prediction algorithms. This combined in silico analysis enhances the precision of identification of functional HCV-specific CTL epitopes. This approach will be applicable to the design of human vaccines not only for HCV, but also for other antigens in which T-cell responses play a crucial role.

The skin is an attractive organ for immunization because of the presence of antigen-presenting cells. Intradermal delivery via tattooing has demonstrated superior vaccine immunogenicity of DNA vaccines in comparison to conventional delivery methods. In this study, we explored the efficacy of tattoo injection of a tumor vaccine based on recombinant Semliki Forest virus replicon particles (rSFV) targeting human papillomavirus (HPV). Tattoo injection of rSFV particles resulted in antigen expression in both the skin and draining lymph nodes. In comparison with intramuscular injection, the overall antigen expression determined at the site of administration and draining lymph nodes was 10-fold lower upon tattoo injection. Delivery of SFV particles encoding the E6 and E7 antigens of human papillomavirus type 16 (SFVeE6,7) via tattooing resulted in HPV-specific cytotoxic T cells and in vivo therapeutic antitumor response. Strikingly, despite the observed lower overall transgene expression, SFVeE6,7 delivered via tattoo injection resulted in higher or equal levels of immune responses as compared to intramuscular injection. The intrinsic immunogenic potential of tattooing provides a benefit for immunotherapy based on an alphavirus.

Human papilloma virus (HPV)-induced cervical cancer constitutively expresses viral E6/E7 oncoproteins and is an excellent target for T cell-based immunotherapy. However, not all tumor-infiltrating T cells confer equal benefit to patients, with epithelial T cells being superior to stromal T cells. To assess whether the epithelial T cell biomarker CD103 could specifically discriminate the beneficial antitumor T cells, association of CD103 with clinicopathological variables and outcome was analyzed in the TCGA cervical cancer data set (n = 304) and by immunohistochemistry (IHC) in an independent cohort (n = 460). Localization of CD103+ cells in the tumor was assessed by immunofluorescence. Furthermore, use of CD103 as a response biomarker was assessed in an in vivo E6/E7+ tumor model. Our results show that CD103 gene expression was strongly correlated with cytotoxic T cell markers (e.g. CD8/GZMB/PD1) in the TCGA series. In line with this, CD103+ cells in the IHC series co-expressed CD8 and were preferentially located in cervical tumor epithelium. High CD103+ cell infiltration was strongly associated with an improved prognosis in both series, and appeared to be a better predictor of outcome than CD8. Interestingly, the prognostic benefit of CD103 in both series seemed limited to patients receiving radiotherapy. In a preclinical mouse model, HPV E6/E7-targeted therapeutic vaccination in combination with radiotherapy increased the intratumoral number of CD103+ CD8+ T cells, providing a potential mechanistic basis for our results. In conclusion, CD103 is a promising marker for rapid assessment of tumor-reactive T cell infiltration of cervical cancers and a promising response biomarker for E6/E7-targeted immunotherapy.

High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated POLE exonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8+ (90% and 69%), PD-1+ (73% and 69%) and PD-L1+ immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8+ cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.

In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and ensured by dedicated funding. Biomarker validation and development should be made public and transparent to ensure rapid progresses with positive outcomes for patients. Guidelines/templates for patients’ informed consent are needed. Importantly for the public, recognized goals are to increase the involvement of advocates and to improve the reporting of translational data in a forum accessible to patients.

Although current cytomorphology-based cervical cancer screening has reduced the incidence of cervical cancer, Papsmears are associated with high false positive and false negative rates. This has spurred the search for new technologies to improve current screening. New methodologies are automation of Pap-smear analysis, addition of new biological or molecular markers to traditional cytology or using these new markers to replace the current screening method. In this overview we will summarize data on cervical cancer epidemiology and etiology and the current cervical cancer screening approach. Available data on new screening approaches, such as quantitative cytochemistry, detection of loss of heterozygosity (LOH) and hypermethylation analysis will be reviewed.We discuss the potential of these approaches to replace or augment current screening. When available, data on cost– effectiveness of certain approaches will be provided. In short, Human Papillomavirus (HPV) DNA detection stands closest to implementation in nation-wide screening programs of all markers reviewed. However, specificity is low in women aged

Unraveling the mechanisms used by the immune system to fight cancer development is one of the most ambitious undertakings in immunology. Detailed knowledge regarding the mechanisms of induction of tolerance and immunosuppression within the tumor microenvironment will contribute to the development of highly effective tumor eradication strategies. Research within the last few decades has shed more light on the matter. This paper aims to give an overview on the current knowledge of the main tolerance and immunosuppression mechanisms elicited within the tumor microenvironment, with the focus on development of effective immunotherapeutic strategies to improve homing and activity of immune effector cells to tumors.

The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a “universal” vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray. Expression of tumor antigens p53, SP17, survivin, WT1, and NY-ESO-1 was observed in 120 (48.0%), 173 (68.9%), 208 (90.0%), 129 (56.3%), and 27 (11.0%) of 270 tumor specimens, respectively. In 93.2% of EOC, at least one of the investigated tumor antigens was (over)expressed. Expression of MHC class I was observed in 78.1% of EOC. In 3 out 4 primary tumors, (over)expression of a tumor antigen combined with MHC class I was observed. These results indicate that a multiepitope vaccine, comprising these antigens, could serve as a universal therapeutic vaccine for the vast majority of ovarian cancer patients.