Background Pre-metastatic niches composed of mainly myeloid cells are recognized as critical for tumor metastasis. However, whether adaptive immune cells also play an important role in pre-metastatic niche formation remains to be explored.Methods CD4+ T cell accumulation in tumor-free lung tissues from mice bearing subcutaneous mouse tumors was detected by immunofluorescence/confocal microscopy. Tumor-conditioned media (TCM) from MB49-S1pr1high mouse bladder tumor cells or ID8 ovarian tumor cells were administered to tumor-free mice to induce pre-metastatic niche formation. We used mice lacking functional Signal Transducer and Activator of Transcription 3 (STAT3) in T cells and Il17a‒/‒ mice to investigate the roles of STAT3 and interleukin (IL)-17. In vivo time-course experiments were performed to assess whether CD4+ T cell clusters contribute to CD11b+ pre-metastatic clusters. CD4+ T cell migration and chemokine receptor expression assays were employed to identify tumor factors driving CD4+ T cell recruitment. A co-culture system with human MRC-5 lung fibroblasts, healthy donor-derived CD4+ T cells, myeloid cells, and TCM derived from human cancer cells was used to evaluate CD4+ T cell-driven fibroblast activation and IL-17A dependency for myeloid cell migration. Microscopic analyses were performed to confirm CD4+ T cell clusters in tumor-free lymph node tissues from patients with prostate cancer and postmortem lung and liver specimens from patients with ovarian cancer.Results We demonstrate that CD4+ T cells accumulate in tumor-free lungs and promote tumor metastasis in mouse models. CD4+ T-cell pre-metastatic niche formation requires STAT3, which regulates Th17 CD4+ T cells. TCM drives IL-6-dependent CCR4/CCR6 upregulation on naive CD4+ T cells. CD4+ T cell clusters contribute to myeloid cell accumulation, and ablating STAT3 in T cells abrogates both T cell and myeloid cluster formation. IL-17 inhibition reduces myeloid lung infiltration. In human co-cultures, CD4+ T cells amplify TCM-induced fibroblast pre-metastatic niche-like activation and myeloid recruitment in an IL-17A-dependent manner. CD4+ and IL-17+ or p-STAT3+ clusters were also detected in non-metastatic tissues from patients with several cancers.Conclusions CD4+ T cells form pre-metastatic niches through the STAT3-IL-17 axis, contributing to myeloid cell cluster formation, in part through amplifying fibroblast pre-metastatic niche-like activation. STAT3 and IL-17 in CD4+ T cells therefore are important for pre-metastatic niche formation and metastasis.

OBJECTIVE:Cervical cancer is the fourth most common female cancer worldwide. As improved cancer survivorship rates continue, understanding any increased risk for subsequent cancers is vital for surveillance. This study investigates the risk of developing second primary malignancies among women with cervical cancer, along with racial disparities in this risk between non-Hispanic Blacks (Blacks) and non-Hispanic Whites (Whites). METHODS:Using Surveillance, Epidemiology, and End Results data, we identified Black and White women diagnosed with stage I to IV cervical cancer from 2000 to 2021. Risk of second primary malignancy was calculated using standardized incidence ratios, which represent the observed number of cases divided by the expected number of cases after adjusting for age, race, and year of diagnosis. Likelihood ratio tests were used to determine statistical significance in standardized incidence ratios across race and by anatomic and exposure-related group sites. Multi-variate Cox regression and Kaplan-Meier methods were used to compare demographics and clinical factors across race and second primary malignancy status. RESULTS:Among 36,702 patients with cervical cancer, 2639 (7.2%) developed a second primary (524 Blacks and 2115 Whites). Both groups had elevated standardized incidence ratios, with Blacks showing significantly higher standardized incidence ratios than Whites (1.7 vs 1.3, p <.001). Anatomic- and exposure-related sites with the highest overall standardized incidence ratios were (human papillomavirus) HPV-related (6.4), respiratory (2.5), urinary (2.1), smoking-related (2.0), genital (1.9), and radiation-related (1.7) (all p <.05). HPV-related sites had the highest standardized incidence ratios and were significantly higher in Blacks than Whites (13.5 vs 5.3, p <.001). At 10 years, second primary malignancy-free survival (89% vs 91%), overall survival (52% vs 65%), and cancer-specific survival (63% vs 72%) were all lower in Blacks (all p <.001). CONCLUSIONS:Cervical cancer survivors face an elevated risk of second primary malignancies, disproportionately affecting Black patients and HPV-related sites, emphasizing the need for enhanced surveillance and targeted follow-up to address persistent disparities.

Despite endocrine therapy (ET), approximately 20–40% of Stage I–III estrogen receptor-positive breast cancer (ER + BC) patients experience recurrence. Recurrence while on ET is indicative of ET resistance. This study aimed to identify differentially expressed genes (DEGs) associated with recurrence during ET (ET resistance) and to explore gene expression differences across PAM50 molecular subtypes. Eighty tumor specimens from 79 patients treated at the City of Hope Comprehensive Cancer Center (2012–2016) were analyzed using NanoString technology. Fourteen patients (17.7%) experienced recurrence over a median follow-up of 68 months (range 35–104 months). Key upregulated DEGs in the recurrence group included EZH2 (log2 fold change[log2FC]: 0.67, p = 0.0017), WNT11 (log2FC: 1.08, p = 0.0088), ITGB6 (log2FC: 0.80, p = 0.0312), and TOP2A (log2FC: 0.79, p = 0.0381). Downregulated DEGs included SNAI2 (log2FC: − 0.63, p = 0.0055), ITPR1 (log2FC: − 0.75, p = 0.0083), CD10 (log2FC: − 0.70, p = 0.0092), PTEN (log2FC: − 0.29, p = 0.0163), VRD (log2FC: − 0.46, p = 0.0184), and WNT5A (log2FC: − 0.76, p = 0.0272). EZH2 and TOP2A were positively correlated with proliferation scores, while WNT11 and ITGB6 emerged as potential biomarkers independently associated with recurrence. These findings suggest novel biomarker candidates that could help overcome ET resistance, reduce recurrence, and improve outcomes in ER + BC.

Cancer disparities among Latinos in the United States persist as a significant public health challenge, characterized by inequitable outcomes throughout the cancer continuum. Latinos experience elevated rates and poorer prognoses in certain cancers compared to other populations, driven by complex, multilevel interactions involving environmental exposures, genetic factors, cultural practices, and systemic inequalities. Recognizing the substantial heterogeneity among Latinos—including differences in national origin, immigration experiences, socioeconomic status, language, and race—is crucial, as oversimplification risks masking key disparities. To comprehensively understand these dynamics, the Task Force: Latino Researchers Against Cancer (TFLRAC) convened specialists in oncology, public health, and behavioral sciences to systematically examine the multiple influences contributing to these disparities. Findings highlight environmental hazards, genetic susceptibilities, cultural stigmas, and linguistic barriers as significant drivers. Systemic issues such as discrimination, colorism, inadequate healthcare coverage, workforce disparities, socioeconomic challenges, and underrepresentation in clinical trials further compound these inequities. Addressing these disparities requires a multifaceted strategy, including targeted research, culturally tailored interventions, and comprehensive policy reforms to improve healthcare access, workforce diversity, and clinical trial inclusion. Collaborative efforts across academia, healthcare systems, community organizations, governmental agencies, and industry partners are imperative to achieve equitable cancer outcomes among Latinos.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. In this study, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared with normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune-reactive tumor microenvironment. Mutations in several switch/sucrose nonfermenting (SWI/SNF) subunits were associated with higher rates of outlier retained introns across tumor types in The Cancer Genome Atlas data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention (IR). Distinct protein-protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Furthermore, SWI/SNF localized to genes, which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides, and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFα and INFγ in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to IR. Furthermore, T-cell activation by novel peptides encoded by these tumor-specific splicing events suggests IR could be a source of tumor-associated antigens in SCCOHT. SIGNIFICANCE:SCCOHT, a rare ovarian cancer, features splicing dysregulation due to SMARCA4 loss that generates immunostimulatory peptides linked to potential immune responses and therapeutic avenues, challenging traditional views of the role of SMARCA4.

Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, PARP inhibitor treatment highly increased intracellular PD-L1 accumulation in both ovarian cancer-patient tumor samples and cell lines. We investigated whether intracellular PD-L1 might play a critical role in ovarian cancer progression. Mutating the PD-L1 acetylation site in PEO1 and ID8Brca1-/- ovarian cancer cells significantly decreased PD-L1 levels and impaired colony formation, which was accompanied by cell cycle G2/M arrest and apoptosis induction. PEO1 and ID8Brca1-/- tumors with PD-L1 acetylation site mutation also exhibited significantly reduced growth in mice. Furthermore, targeting intracellular PD-L1 with a cell-penetrating antibody effectively decreased ovarian tumor-cell intracellular PD-L1 level and induced tumor-cell growth arrest and apoptosis, as well as enhanced DNA damage and STING activation, both in vitro and in vivo. In conclusion, we have shown the critical role of intracellular PD-L1 in ovarian cancer progression.

Distribution of clinical features associated with poor and good prognostic HGSOC patient samples in the TCGA U133A dataset.

[This corrects the article DOI: 10.3389/fpubh.2025.1591074.].

Background: Somatically derived ovarian yolk sac tumors (SD-YSTs) in postmenopausal women are rare and typically present with advanced-stage disease, often carrying a poor prognosis. Case: We describe a 74-year-old woman with stage IIIB SD-YST who underwent complete surgical resection followed by cisplatin-etoposide chemotherapy, with bleomycin omitted due to frailty. Chemotherapy scheduling was modified in real time according to alpha-fetoprotein (AFP) kinetics, with treatment intervals shortened from 21 to 14 days after AFP levels rose between early cycles. Despite dose reductions due to thrombocytopenia, AFP levels normalized after cycle 3, and treatment was discontinued after cycle 4. Outcome: The patient has remained disease-free for over five years with ongoing surveillance. Conclusion: This case underscores the potential for long-term remission in SD-YST with platinum-based therapy, even when standard regimens require modification for older or frail patients. It highlights the value of biomarker-guided treatment adjustments to optimize chemotherapy timing in rare ovarian malignancies.

Background Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment.Methods By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG’s catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition.Results Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors.Conclusions We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.

The response to treatment is substantially varied between individual patients with ovarian cancer. However, chemotherapy treatment plans rarely pay sufficient attention to the mentioned factors. Instead, standardized treatment protocols are usually employed for most ovarian cancer patients. Variations in an individual's sensitivity to drugs significantly limit the effectiveness of treatment in some patients and lead to severe toxicities in others. In the present investigation, a nanotechnology-based approach for personalized treatment of ovarian carcinoma (the most lethal type of gynecological cancer) constructed on the individual genetic profile of the patient's tumor is developed and validated. The expression of predefined genes and proteins is analyzed for each patient sample. Finally, a mixture of the complex nanocarrier-based targeted delivery system containing drug(s)/siRNA(s)/targeted peptide is selected from the pre-synthesized bank and tested in vivo on murine cancer model using cancer cells isolated from tumors of each patient. Based on the results of the present study, an innovative approach and protocol for personalized treatment of ovarian cancer are suggested and evaluated. The results of the present study clearly show the advantages and perspectives of the proposed individual treatment approach.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. (c) 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Objective: Living in a food desert is a known negative health risk, with recent literature finding an associated higher mortality in patients with cancers. Gynecologic cancers have not specifically been studied. We aimed to describe patients with gynecologic cancers who live in a food desert and determine if there is an association between living in a food desert and gynecologic cancer mortality. Methods: The 2013 -2019 California Cancer Registry (CCR) was used to identify patients with endometrial, ovarian, or cervical cancers. Patient residential census tract was linked to food desert census tracts identified by the 2015 United States Department of Agriculture Food Access Research Atlas. Comorbidity data were obtained from the California Office of Statewide Health Planning and Development database (OSHPD). Treatment, diagnosis, and survival outcomes were obtained from the CCR 's variables and compared by food desert status. Five-year disease -specific survival was analyzed by applying Cox proportional hazards analysis. Results: 40,340 gynecologic cancer cases were identified. 60.1 % had endometrial cancer, 23.2 % had ovarian cancer, and 15.9 % had cervical cancer. The average age of the cohort was 59.4 years, 48.0 % was non -Hispanic White, 50.3 % was privately insured, and 6.8 % of lived in a food desert. Living in a food desert was associated with higher disease -specific mortality for patients with gynecologic cancers (endometrial cancer HR 1.43p < 0.001 95 % CI 1.22 -1.68; ovarian cancer HR 1.47p < 0.001 95 % CI 1.27 -1.69; cervical cancer HR 1.24p = 0.045 95 % CI 1.01 -1.54). Conclusion: Patients living in food deserts had worse disease -specific survival, making access to food a modifiable risk factor that may result in mitigating gynecologic cancer disparities.