Both clinical-pathological and experimental studies have shown that chemokines play a key role in activating the immune checkpoint modulator in cervical cancer progression and are associated with prognosis in tumor cell proliferation, invasion, angiogenesis, chemoresistance, and immunosuppression. Therefore, a clear understanding of chemokines and immune checkpoint modulators is essential for the treatment of this disease. This review discusses the origins and categories of chemokines and the mechanisms that are responsible for activating immune checkpoints in cervical dysplasia and cancer, chemokines as biomarkers, and therapy development that targets immune checkpoints in cervical cancer research.

Seroma development after breast cancer surgery is the most common postoperative complication seen after mastectomy but neither its origin nor its cellular composition is known. To investigate the assumption of immunological significance, one of the first aims of this pilot study is to describe the cellular content of collected seroma fluids and its corresponding serum in patients with simple mastectomy after needle aspiration, as well as the serum of healthy controls. The content of red blood cells (RBC) was measured by haemato-counter analyses, and the lymphocyte identification/quantification was conducted by flow cytometry analyses in seroma fluid (SFl) and the sera of patients (PBp) as well as controls (PBc). Significantly lower numbers of RBCs were measured in SFl. Cytotoxic T cells are significantly reduced in SFl, whereas T helper (Th) cells are significantly enriched compared to PBp. Significantly higher numbers of Th2 cells were found in SFl and PBp compared to PBc. The exact same pattern is seen when analyzing the Th17 subgroup. In conclusion, in contrast to healthy controls, significantly higher Th2 and Th17 cell subgroup-mediated immune responses were measured in seroma formations and were further confirmed in the peripheral blood of breast cancer (including DCIS) patients after simple mastectomy. This could lead to the assumption of a possible immunological cause for the origin of a seroma.

New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In this study, we aimed to investigate the expression of EP4 in vulvar cancer tissue and its association with clinicopathological data and its prognostic relevance on survival. Immunohistochemistry was performed on tumor specimens of 157 patients with vulvar cancer treated in the Department of Obstetrics and Gynecology, Ludwig-Maximilian-University of Munich, Germany, between 1990 and 2008. The expression of EP4 was analyzed using the well-established semiquantitative immunoreactivity score (IRS) and EP4 expression levels were correlated with clinicopathological data and patients’ survival. To specify the tumor-associated immune cells, immunofluorescence double staining was performed on tissue samples. In vitro experiments including 5-Bromo-2′-Deoxyuridine (BrdU) proliferation assay and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) viability assay were conducted in order to examine the effect of EP4 antagonist L-161,982 on vulvar carcinoma cells. EP4 expression was a common finding in in the analyzed vulvar cancer tissue. EP4 expression correlated significantly with tumor size and FIGO classification and differed significantly between keratinizing vulvar carcinoma and nonkeratinizing carcinoma. Survival analysis showed a significant correlation of high EP4 expression with poorer overall survival (p = 0.001) and a trending correlation between high EP4 expression and shorter disease-free survival (p = 0.069). Cox regression revealed EP4 as an independent prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. In order to evaluate EP4 as a prognostic marker and possible target for endocrinological therapy, more research is needed on the influence of EP4 in the tumor environment and its impact in vulvar carcinoma.

There exists a variety of studies about tumor-infiltrating immune cells (TIICs) in cervical cancer, but their prognostic value in correlation with the histopathological subtype has never been investigated. Therefore, the aim of this study was to quantify TIICs in a panel of 238 sporadic cervical cancers and investigate the correlation with cervical cancer subtype and patient survival. TIICs levels were significantly increased in the subgroup of CSCC (191 samples) in comparison to CAC (47 samples). In CSCC, TIICs’ infiltration showed a negative correlation with age, FIGO stage and with the histone protein modification H3K4me3. Moreover, in CAC, it was positively correlated with p16 and with the glucocorticoid receptor and inversely correlated with the MDM2 protein and with H3K4me3. Interestingly, immune infiltration was an independent positive prognosticator for disease-free survival (DFS) in patients with CSCC, those bearing tumors with the strongest TIICs infiltration showing the better DFS. Altogether, the present study provides a differentiated overview of the relations between TIIC levels and prognosis in patients with CSCC vs. patients with CAC.

The role of progesterone receptor A (PRA) for the survival outcome of cervical cancer patients is ambiguous. In mouse models, it has been shown that PRA plays a rather protective role in cancer development. The aim of this study was to assess its expression by immunohistochemistry in 250 cervical cancer tissue samples and to correlate the results with clinicopathological parameters including patient survival. PRA expression was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) classification scores. PRA was significantly overexpressed in adenocarcinomas compared to squamous epithelial carcinoma subtypes. Correlation analyses revealed a trend association with the HPV virus protein E6, a negative correlation with p16 and a positive correlation with EP3. PRA expression was also associated with the expression of RIP140, a transcriptional coregulator that we previously identified as a negative prognostic factor for survival in cervical cancer patients. Univariate survival analyses revealed PRA as a negative prognosticator for survival in patients with cervical adenocarcinoma. Multivariate analyses showed that simultaneous expression of RIP140 and PRA was associated with the worst survival, whereas with negative RIP140, PRA expression alone was associated with the best survival. We can therefore assume that the effect of nuclear PRA on overall survival is dependent upon nuclear RIP140 expression.

The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.