A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.

High tumour stromal content has been found to predict adverse clinical outcome in a range of epithelial tumours. The aim of this study was to assess the prognostic significance of tumour-stroma ratio (TSR) in endometrial adenocarcinomas and investigate its relationship with other clinicopathological parameters. Clinicopathological and 5-year follow-up data were obtained for a retrospective series of endometrial adenocarcinoma patients (n = 400). TSR was measured using a morphometric approach (point counting) on digitised histologic hysterectomy specimens. Inter-observer agreement was determined using Cohen’s Kappa statistic. TSR cut-offs were optimised using log-rank functions and prognostic significance of TSR on overall survival (OS) and disease-free survival (DFS) were determined using Cox Proportional Hazards regression analysis and Kaplan-Meier curves generated. Associations of TSR with other clinicopathological parameters were determined using non-parametric tests followed by Holm-Bonferroni correction for multiple comparisons. TSR as a continuous variable associated with worse OS (P = 0.034) in univariable Cox-regression analysis. Using the optimal cut-off TSR value of 1.3, TSR-high (i.e. low stroma) was associated with worse OS (HR = 2.51; 95 % CI = 1.22–5.12; P = 0.021) and DFS (HR = 2.19; 95 % CI = 1.15–4.17; P = 0.017) in univariable analysis. However, TSR did not have independent prognostic significance in multivariable analysis, when adjusted for known prognostic variables. A highly significant association was found between TSR and tumour grade (P < 0.001) and lymphovascular space invasion (P < 0.001), both of which had independent prognostic significance in this study population. Low tumour stromal content associates with both poor outcome and with other adverse prognostic indicators in endometrial cancer, although it is not independently prognostic. These findings contrast with studies on many - although not all - cancers and suggest that the biology of tumour-stroma interactions may differ amongst cancer types.

Results of recent clinical trials using the immune check point inhibitors (ICI) pembrolizumab or dostarlimab with/without lenvatinib has led to their approval for specific molecular subgroups of advanced recurrent endometrial cancer (EC). Herein, we summarise the clinical data leading to this first tissue-agnostic approval. As this novel therapy is not yet available in the United Kingdom standard care setting, we explore the strengths, weaknesses, opportunities, and threats (SWOT) of ICI treatment in EC. Major databases were searched focusing on clinical trials using programmed cell death protein 1 (PD-1) and its ligand (PD-L1) ICI which ultimately contributed to anti-PD-1 approval in EC. We performed a data quality assessment, reviewing survival and safety analysis. We included 15 studies involving 1609 EC patients: 458 with mismatch repair deficiency (MMRd)/microsatellite instability-high (MSI-H) status and 1084 with mismatch repair proficiency/microsatellite stable (MMRp/MSS) status. Pembrolizumab/dostarlimab have been approved for MMRd ECs, with the addition of lenvatinib for MMRp cases in the recurrent setting. Future efforts will focus on the pathological assessment of biomarkers to determine molecular phenotypes that correlate with response or resistance to ICI in order to identify patients most likely to benefit from this treatment.

Cytokine-hormone network deregulations underpin pathologies ranging from autoimmune disorders to cancer, but our understanding of these networks in physiological/pathophysiological states remains patchy. We employed Bayesian networks to analyze cytokine-hormone interactions in vivo using murine lactation as a dynamic, physiological model system. Circulatory levels of estrogen, progesterone, prolactin and twenty-three cytokines were profiled in post partum mice with/without pups. The resultant networks were very robust and assembled about structural hubs, with evidence that interleukin (IL)-12 (p40), IL-13 and monocyte chemoattractant protein (MCP)-1 were the primary drivers of network behavior. Network structural conservation across physiological scenarios coupled with the successful empirical validation of our approach suggested that in silico network perturbations can predict in vivo qualitative responses. In silico perturbation of network components also captured biological features of cytokine interactions (antagonism, synergy, redundancy). These findings highlight the potential of network-based approaches in identifying novel cytokine pharmacological targets and in predicting the effects of their exogenous manipulation in inflammatory/immune disorders.

Background Endometrial carcinoma (EC) is the most common uterine cancer in the USA with rising incidence and mortality rates. Microcephalin 1 (MCPH1) and Bromodomain Containing 4 (BRD4) are DNA repair proteins involved in maintaining genomic stability and chromatin regulation. Dysregulated expression of these genes has been linked to poorer patient outcomes in EC. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a promising treatment for EC. However, response rates are variable, indicating the need to identify novel biomarkers to improve patient stratification for immunotherapy. This study assessed the association between MCPH1 and BRD4 mRNA and protein expression and EC clinical and molecular biomarkers, particularly immune markers. Methods Immunohistochemistry was performed on 403 ECs. Nuclear staining was quantified using Qu-Path software to generate H Scores. Both continuous and categorised data analysis were performed for clinical parameters, p53 mutational status, mismatch repair deficiency and ICI related markers PD-1, PD-L1 and CD8. Statistical analysis included Chi-squared, Fisher’s exact, Mann-Whitney U, Kruskal Willis, Kaplan-Meier and Cox regression. Results High MCPH1 (p=0.034) and BRD4 (p=0.044) protein expression levels were both significantly associated with reduced disease specific survival (DSS). High MCPH1 protein levels were also an independent predictor of DSS. MCPH1 protein expression showed no significant association with clinical parameters. By contrast, high BRD4 protein expression was significantly associated with non-endometrioid EC (p=0.003), high tumour grade (p=0.052) and lymphovascular space invasion (p=0.052). MCPH1 protein upregulation correlated significantly with CD8 infiltrate, PD-L1, PD-1, and mismatch repair proficiency (MMRp). In addition, BRD4 protein expression correlated with p53 mutation, CD8 infiltrate, PD-L1 and PD-1 expression. Conclusions High MCPH1 and BRD4 protein expression was associated with immune activation markers and worse survival in EC, suggesting their potential as prognostic biomarkers. Both MCPH1 and BRD4 may also represent potential predictive markers for response to ICI therapy in EC.