Sahar Salehi

Adaptive NK Cells Exhibit Tumor-Specific Immune Memory and Cytotoxicity in Ovarian Cancer

Abstract Adaptive NK (aNK) cells have emerged as a subset of NK cells with memory-like properties and specific cytotoxicity, offering promising therapeutic potential in cancer immunotherapy. In this study, we explored the role of aNK cells in high-grade serous ovarian cancer, focusing on their ability to establish tumor-specific immune memory and effectively target autologous tumors. Through a combination of in silico, in vitro, and ex vivo approaches, we demonstrated that aNK cells, in contrast to conventional NK cells, exhibit recall responses, specific cytotoxicity, and preferential infiltration into the tumor microenvironment. Our data revealed that aNK cells interact with dendritic cells within the tumor microenvironment via the HLA-E/NKG2C axis and CXCR2 signaling, contributing to their memory formation and tumor-targeting capabilities. These findings suggest that aNK cells could serve as potent agents in NK cell–based immunotherapies, particularly in solid tumors such as high-grade serous ovarian cancer, in which they resist immunosuppressive signals and maintain robust antitumor activity. This study provides new insights into the adaptive-like properties of aNK cells, underscoring their potential for advancing cancer immunotherapy strategies.

Extensive cytoreductive surgery in stage IV ovarian cancer may not be a justified treatment strategy

Complete macroscopic surgical cytoreduction improves survival in advanced ovarian cancer. However, our previous results suggest that the survival benefits of aggressive surgery to achieve complete macroscopic resection may vary across different subgroups. This study aimed to identify a potential poor-prognosis subgroup among patients with complete macroscopic resection. This cohort study included all patients with advanced ovarian cancer who underwent complete macroscopic resection in a public and centralized health care system setting. Two 3-year cohorts were compared: pre-implementation (cohort 1, n = 101) and post-implementation (cohort 2, n = 172) of a very high surgical proficiency setting. Overall survival was compared by relative risks (RR) stratified by stage and surgical extent. Cox regression estimated hazard ratios (HR) adjusted for relevant covariates. In patients with stage IV, median survival was 33 (cohort 2) vs 47 months (cohort 1), 7-year RR 1.01 (95 % CI 0.78 to 1.31). When extensive surgery was required in stage IV median survival was 27 (cohort 2) vs 58 months (cohort 1), 5-year RR 0.91 (95 % CI 0.81 to 1.01). By contrast, in stage III, median survival was 93 (cohort 2) vs 59 (cohort 1) months, 7-year RR 0.76 (95 % CI 0.59 to 0.98), with the greatest difference when less extensive surgery was required; Not reached vs 65 months, 7-year RR 0.62 (95 % CI, 0.43 to 0.88). Adjusted analysis confirmed improved survival in cohort 2 only after less extensive surgery, HR 0.56 (95 % CI, 0.33-0.95). The implementation of a very high surgical proficiency setting was not associated with improved survival in patients with stage IV despite complete macroscopic resection, as opposed to patients with stage III.

Surgery performed later in the week is associated with failure to achieve complete radical surgical resection in advanced ovarian cancer

Efficacy and Safety of Glycosphingolipid SSEA-4 Targeting CAR-T Cells in an Ovarian Carcinoma Model

Abstract Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized stage-specific embryonic antigen-4 (SSEA-4) cell-surface glycolipid as a target for CAR T-cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed preclinically in vitro and in vivo for antitumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4–positive cells in all the tested cancer cell lines, whereas SSEA-4–negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific antitumor response at all the CAR T-cell doses used. At high T-cell doses, CAR T cell–treated mice showed signs of health deterioration after a follow-up period. However, the severity of toxicity was reduced with a delayed onset when lower CAR T-cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR T-cell therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.

Surgery performed later in the week is associated with inferior survival in advanced ovarian cancer

Complete macroscopic resection without any residual tumour after completion of surgery is a strong prognostic factor in advanced epithelial ovarian cancer (EOC). It has previously been reported that surgery performed later in the week is associated with failure to achieve complete macroscopic resection. Our objective was to examine if weekday of surgery influences oncologic outcome. This population-based observational study included 100% of all women diagnosed with advanced-stage invasive epithelial ovarian cancer between 2009-2011 and 2014-2016 in the Stockholm/Gotland County of Sweden. The association between weekday of surgery and survival was analysed with proportional hazards regression yielding hazard ratios (HR) with 95% confidence intervals (CI), adjusted for predefined confounders. Out of 1066 identified women, 524 with advanced stage EOC treated with surgery were included in the final analysis. Surgery performed Wednesday to Thursday was associated with an increased hazard of death (HR 1.28, 95% CI 1.04-1.58, The increased mortality associated with surgery that is performed later in the week suggests that surgery for advanced ovarian cancer is best conducted early in the week.

Perioperative trajectories of acute-phase proteins and their association with major postoperative complications in advanced ovarian cancer

Acute-phase proteins (APPs) reflect systemic inflammation and nutritional status, yet their perioperative trajectories and clinical utility as biomarkers of outcome in advanced ovarian cancer (aEOC) remain unclear. We aimed to characterise perioperative APP fluctuations and assess their associations with postoperative complications. This observational study included patients undergoing cytoreductive surgery for aEOC across two prospective studies (n = 274). Serial serum albumin, transthyretin, C-reactive protein (CRP), fibrinogen, and procalcitonin were measured preoperatively and on postoperative days (PoD) 1, 3, and 5. Associations between APP levels and major postoperative complications, classified by Clavien-Dindo (CD ≥ III), were examined using multivariable logistic regression. Length of stay (LOS) was evaluated for biomarkers showing significant associations. Predictive thresholds were derived by ROC analysis. Positive APPs peaked postoperatively (CRP and fibrinogen on PoD 3; procalcitonin on PoD 1), while negative APPs reached nadirs on PoD 3. Neither preoperative albumin (>35 g/L) nor transthyretin (>0.2 g/L) predicted major postoperative complications. In contrast, elevated CRP measured on PoD 3 was associated with both major postoperative complications, OR 2.78 (95% CI 1.45-5.48) and prolonged LOS (>7 days) OR 3.0 (95% CI 1.67-5.47), with optimal cut-offs of ≥287 mg/L and ≥322 mg/L respectively (AUC 0.80). Preoperative APPs were not associated with postoperative outcomes in this cohort. CRP measured on postoperative day 3 was the most informative biomarker associated with major postoperative complications and prolonged hospital stay after cytoreductive surgery for advanced ovarian cancer and may support postoperative surveillance and recovery assessment when interpreted alongside clinical findings.

Pelvic exenteration for vulvar cancer: contemporary outcomes from a multinational cohort study

Women with vulvar cancer are considerably older than those with other gynaecological malignancies, raising concerns about the tolerability of radical surgery. Yet, for locally advanced or recurrent disease, pelvic exenteration may be the only curative option. Robust evidence to guide decision-making in this population is lacking. This multicentre observational cohort study used data from the COREPEX registry including women who underwent anterior or total pelvic exenteration between 2005 and 2023 across 20 European tertiary referral centres. The primary outcome was overall survival (OS); secondary outcomes were progression-free survival (PFS) and major postoperative complications. Associations were assessed using multivariable Cox and binomial regression models adjusted for relevant covariates. Among 861 women, 79 (9.2%) had vulvar cancer. Median follow-up was 49 months for OS and 40 months for PFS. Women with vulvar cancer were older and more often overweight. Five-year OS was 32% (95% CI, 19-46) in vulvar cancer versus 29% (95% CI, 25-34) in other cancers, adjusted HR 1.05 (95% CI, 0.75-1.46). Five-year PFS was 34% versus 29%, adjusted HR 0.96 (95% CI, 0.69-1.34). Major complications occurred in 33% vs 29%, adjusted RR 1.12 (95% CI, 0.77-1.58). Lymph node metastases, positive margins, and recurrent or persistent disease independently predicted poorer survival. Despite their older age, women with vulvar cancer had survival and morbidity comparable to those with other gynaecological malignancies. These findings support pelvic exenteration as a curative option for selected women with vulvar cancer when complete resection is feasible.