Background Novel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although therapies targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance their efficacy. Methods Blood samples, tumor specimens, and peritumorous (PT) tissues were obtained from patients with CC. The inhibitory receptor expression and phenotypical analysis of CD8+ T cells in CC specimens were analyzed by flow cytometry. The ligands of CD96 expressed by tumor cells were measured by immunohistochemistry and immunofluorescence. Sensitivity to pembrolizumab was evaluated by an ex vivo treatment assay based on the single-cell culture of CC specimens. The efficacies of PD-1 and/or CD96 blockades were explored using an ex vivo treatment assay and an human papillomavirus-positive TC-1 xenograft mouse model in vivo. Results We found that CD96 expression was elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients with CC who were insensitive to the PD-1 blockade. These CD96-expressing CD8+ TILs often coexpressed PD-1. The ratio of the CD96+CD8+/CD96−CD8+ T-cell gene signature from the scRNA-seq data was significantly associated with the poor survival of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma. The costimulatory receptor CD226, which competes with CD96, was downregulated in tumors compared with blood and PT tissue. CD96 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) were upregulated on intratumoral CD8+ T cells. The CD226/CD96/TIGIT signaling ligands were widely expressed in CC tumor tissues. Phenotypical profiling showed that PD-1+CD96+CD8+ TILs exhibited a terminally exhausted effector phenotype with high levels of T-cell immunoglobulin mucin receptor 3 (TIM-3) and granzyme B (GZMB) and extremely low levels of proinflammatory cytokines and cytotoxic molecules. PD-1+CD96 cells exhibited a precursor exhausted phenotype with TCF-1 positivity. CD96 was further upregulated by CD8+ TILs on PD-1 blockade. Treatment with the CD96 blockade significantly enhanced the PD-1 blockade to blunt tumor growth and improve the function of CD8+ TILs in both mouse and CC specimen models. Conclusions Our findings showed that CD96 and PD-1 cooperatively and negatively regulate the function of CD8+ TILs, and CD96 blockade has promise for use in combination with PD-1 blockade for the treatment of CC.

106 Background: Current first-line standard therapy (SOC) for R/M CC is platinum-based chemotherapy +/- bevacizumab (bev). AK104 monotherapy has shown promising efficacy and tolerable toxicity in pretreated R/M CC (NCT04380805). In this study, we report the efficacy and safety of AK104 combined with SOC for the first-line treatment of R/M CC (NCT04868708). Methods: The multicenter, open-label, phase II study enrolled R/M CC pts without previous systemic therapy. Eligible pathological types were squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma. Pts were assigned to 3 cohorts (A-15/A-10: AK104 15/10 mg/kg + PTX 175mg/m² + DDP 50 mg/m²/CBP AUC 5, q3w; B-10: AK104 10 mg/kg + PTX 175 mg/m² + DDP 50 mg/m²/CBP AUC 5 + bev 15 mg/kg, q3w). All pts received AK104 until PD or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included ORR, PFS per RECIST1.1, and OS, etc. Results: 45 pts were enrolled at 6 centers from Jun 3, 2021, to Nov 5, 2021. As of Jan 10, 2022, we assessed safety in all pts and efficacy in pts with at least one tumor assessment result. TRAEs of any grade occurred in 43 (95.6%) pts. Grade ≥3 TRAEs occurred in 23 (51.1%) pts. The most common TRAEs were anemia (55.6%), white blood cell count decreased (46.7%), rash (24.4%), and hypoesthesia (24.4%). The most common grade ≥ 3 TRAEs were anemia (15.6%), white blood cell count decreased (11.1%), neutrophil count decreased (8.9%), and platelet count decreased (8.9%). TRSAE occurred in 17 (37.8%) pts. IrAEs of any grade, assessed by INV, occurred in 24 (53.3%) pts. Grade ≥ 3 irAE occurred in 8 (17.8%) pts. One death due to hemorrhagic shock occurred in cohort B-10 and was judged as treatment-related. ORR were 73.3% (11/15) for A-15, 68.8% (11/16) for A-10, 92.3% (12/13) for B-10, respectively. The response to the treatment was favorable regardless of CPS (Table). PFS or OS data are not mature by cut-off date. Conclusions: AK104 combined with standard therapy was well tolerated, with encouraging antitumor activity in pts with R/M CC. Meanwhile, long-term safety evaluation still needs following up. A phase III trial is ongoing to evaluate the efficacy of AK104 plus standard therapy in first-line treatment for R/M CC (NCT04982237). Clinical trial information: NCT04868708. [Table: see text]

Ferroptosis, a newly discovered iron-dependent form of cell death, contributes to various pathologies; however, the prognostic value of ferroptosis-related genes (FRGs) in cervical cancer (CC) remains unclear. Herein, we identified 15 differentially expressed FRGs based on data from The Cancer Genome Atlas database. Ten FRGs that correlated with prognosis were screened by univariate Cox regression analysis. The least absolute shrinkage and selection operator regression model was performed to develop a novel prognostic signature. A four-gene model was built to separate samples into high-risk and low-risk groups. Overall survival was lower in the high-risk group than in the low-risk group (p < 0.05). Receiver operating characteristic curve showed a good diagnostic efficiency of the signature. The risk score was identified as an independent prognostic factor via multivariate Cox regression. A functional analysis further revealed a difference in the immune status between the two risk groups. To conclude, we constructed a novel prognostic signature based on FRGs. Targeting ferroptosis may represent a promising approach for the treatment of CC. Grapical Abstract

Methods: We collected the clinical data of 260 patients admitted to the hospital from April 2003 to September 2019 with pathologically confirmed intravenous leiomyomatosis (IVL) and followed up with these patients regularly. Univariate and multivariate logistic regression analyses were carried out on the relevant recurrence factors.Results: A total of 166 patients were regularly followed up, the median follow‐up time was 36 (range 2–168) months, 14 (5.4%) patients eventually relapsed, and the median recurrence time was 8.5 (range 2–42) months. The univariate analysis showed that age (p = 0.003) and surgical type (p < 0.001) were associated with recurrence, and multivariate regression analysis demonstrated that surgical type was the only factor associated with recurrence (p < 0.001, OR 20.01).Conclusions: The use of gonadotrophin releasing hormone agonist (GnRHa) cannot reduce the postsurgical recurrence rate of patients with UIVL. Compared to total hysterectomy and bilateral salpingo‐oophorectomy (TH‐BSO), total hysterectomy (TH) does not increase the odds of recurrence, but the chance of recurrence with tumorectomy (TE) is 20 times higher than that of TH‐BSO.