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Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8 + effector T (T EFF ) cells and TIM3 + PD1 + , hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8 + T cells. Conversely, CD8 + T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1 + PD1 + T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8 + T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that – at odds with NSCLC – HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1 + PD1 + CD8 + T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC. Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.

Secondary tumors of the ovary account for 10–25% of all ovarian malignancies. The most common tumors that give rise to ovarian metastases include breast, colorectal, endometrial, stomach, and appendix cancer. The correct diagnosis of secondary ovarian tumors may be challenging as they are not infrequently misdiagnosed as primary ovarian cancer, particularly in the case of mucinous adenocarcinomas. The distinction from the latter is essential, as it requires different treatment. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extra-ovarian metastases and, furthermore, may suggest the primary tumor site. Despite extensive study, some cases remain equivocal even after assessing a broad spectrum of antigens. Therefore, gene expression profiling represents an approach able to further discriminate equivocal findings, and one that has been proven effective in determining the origin of cancer of unknown primary site. The available data concerning secondary ovarian tumors is rather limited owing to the relative heterogeneity of this group and the practical absence of any prospective trials. However, several intriguing questions are encountered in daily practice, including rational diagnostic workup, the role of cytoreductive surgery, and consequent adjuvant chemotherapy. This review seeks to address these issues comprehensively and summarize current knowledge on the epidemiology, pathogenesis, and management of secondary ovarian tumors, including further discussion on the different pathways of metastatisation, metastatic organotropism, and their possible molecular mechanisms.

Background The study aimed to evaluate the impact of integrating molecular classification with imaging-based preoperative staging on risk stratification prediction in endometrial cancer patients in accordance with ESGO/ESTRO/ESP (European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology) 2021 guidelines. Methods A retrospective cohort of 143 endometrial cancer patients was analyzed to assess changes in preoperative risk stratification after incorporating molecular classification into clinical evaluation. Preoperative clinical staging was primarily based on transvaginal ultrasound imaging. The overall agreement between preoperative risk group estimates (with/without molecular classification) and final postoperative outcomes was assessed using weighted Cohen’s Kappa, with bootstrap 95% confidence intervals and quadratic weights. Results The addition of molecular classification significantly improved preoperative risk stratification accuracy (from 59.4 to 73.4%), particularly for patients post-operatively classified as high-risk. Kappa values indicated an improvement in overall agreement between preoperative and postoperative risk stratification following the addition of molecular classification, from 0.551 (95% CI: 0.430–0.671) to 0.767 (95% CI: 0.675–0.849). The non-overlapping confidence intervals indicated statistical significance. Preoperative assessment without molecular input tended to underestimate risk stratification. However, 26.6% of patients remained misclassified due to other factors, mostly within the intermediate and high-intermediate risk groups. Conclusions Incorporating molecular classification enhances preoperative risk stratification and has the potential to tailor surgical treatment. Further validation through prospective multicentric studies is needed to support our findings.

BackgroundStandard treatment of oropharyngeal squamous cell carcinoma (OPSCC) is associated with high morbidity, whereas immunotherapeutic approaches using PD-1:PD-L1 checkpoint blockade only show moderate response rates in OPSCC patients. Therefore, a better stratification of patients and the development of novel therapeutic protocols are crucially needed. The importance of tumor-infiltrating B cells (TIL-Bs) in shaping antitumor immunity remains unclear; therefore, we analyzed frequency, phenotype, prognostic value and possible roles of TIL-Bs in OPSCC.MethodsWe utilized transcriptomic analysis of immune response-related genes in 18 OPSCC samples with respect to human papillomavirus (HPV) status. The density and localization of CD20+, CD8+ and DC-LAMP+ cells were subsequently analyzed in 72 tissue sections of primary OPSCC samples in relation to patients’ prognosis. The immunohistochemical approach was supplemented by flow cytometry-based analysis of phenotype and functionality of TIL-Bs in freshly resected primary OPSCC tissues.ResultsWe observed significantly higher expression of B cell-related genes and higher densities of CD20+ B cells in HPV-associated OPSCC samples. Interestingly, CD20+ TIL-Bs and CD8+ T cells formed non-organized aggregates with interacting cells within the tumor tissue. The densities of both intraepithelial CD20+ B cells and B cell/CD8+ T cell interactions showed prognostic significance, which surpassed HPV positivity and CD8+ TIL density in stratification of OPSCC patients. High density of TIL-Bs was associated with an activated B cell phenotype, high CXCL9 production and high levels of tumor-infiltrating CD8+ T cells. Importantly, the abundance of direct B cell/CD8+ T cell interactions positively correlated with the frequency of HPV16-specific CD8+ T cells, whereas the absence of B cells in tumor-derived cell cultures markedly reduced CD8+ T cell survival.ConclusionsOur results indicate that high abundance of TIL-Bs and high density of direct B cell/CD8+ T cell interactions can predict patients with excellent prognosis, who would benefit from less invasive treatment. We propose that in extensively infiltrated tumors, TIL-Bs might recruit CD8+ T cells via CXCL9 and due to a highly activated phenotype contribute by secondary costimulation to the maintenance of CD8+ T cells in the tumor microenvironment.

A high density of tumor-infiltrating CD8 + T cells and CD20 + B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP + DCs is robustly associated with an immune contexture characterized by T H 1 polarization and cytotoxic activity. We showed that both mature DCs and CD20 + B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP + DCs and CD20 + B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP + DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity.

BackgroundAdjuvanticity, which is the ability of neoplastic cells to deliver danger signals, is critical for the host immune system to mount spontaneous and therapy-driven anticancer immune responses. One of such signals, i.e., the exposure of calreticulin (CALR) on the membrane of malignant cells experiencing endoplasmic reticulum (ER) stress, is well known for its role in the activation of immune responses to dying cancer cells. However, the potential impact of CALR on the immune contexture of primary and metastatic high-grade serous carcinomas (HGSCs) and its prognostic value for patients with HGSC remains unclear.MethodWe harnessed a retrospective cohort of primary (no = 152) and metastatic (no = 74) tumor samples from HGSC patients to investigate the CALR expression in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 302 HGSC samples was used as a confirmatory approach.ResultsWe demonstrate that CALR exposure on the surface of primary and metastatic HGSC cells is driven by a chemotherapy-independent ER stress response and culminates with the establishment of a local immune contexture characterized by TH1 polarization and cytotoxic activity that enables superior clinical benefits.ConclusionsOur data indicate that CALR levels in primary and metastatic HGSC samples have robust prognostic value linked to the activation of clinically-relevant innate and adaptive anticancer immune responses.

BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.MethodsRNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples.Results1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome.ConclusionsImmunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.

Background Extrapulmonary small cell neuroendocrine carcinoma (EP-SC) is a rare malignancy with a poor prognosis. In our study, one hundred and thirty-eight EP-SCNC tissue samples underwent a complex analysis. Method Multicentric study included 138 high-grade small cell carcinomas exhibiting neuroendocrine morphology without known pulmonary involvement. Using TMA, we studied the possible benefit of TTF-1 (DAKO, clone 8G7G3/1, dilution 1:200), CDX-2 (DAKO, ready to use kit DAK-CDX2), PAX-8 (Cell Marque, polyclonal, dilution 1:50) and GATA-3 (Cell Marque, clone L50-823, 1:200) immunohistochemical analyses for determining the primary site of EP-SCNC origin. For statistical analyses, the Kaplan-Meier, the Cox regressions analyses, the Pearson chi-square test and the Fisher’s exact test were used. Results The median survival of our cohort was 11.5 months. Patients younger than 70 years had significantly better overall survival ( p  = 0.024). Across the full cohort, CDX-2 positivity was found in 19 tumors (13.9%), TTF-1 in 35 tumors (25.7%), PAX-8 in 63 tumors (46.3%) and GATA-3 in 8 tumors (6.5%), regardless of tumor origin. The expression of CDX-2, PAX-8 and GATA-3 did not differ significantly among different organ systems ( p  = 0.2; 0.3 and 0.12), respectively. The expression of TTF-1 differed significantly in tumors from various sites of origin ( p  = 0.009), expressed more often in breast, pancreatic, and genitourinary tumors. Interestingly, TTF-1 expression proved to have a negative prognostic impact relative to patient survival (age-adjusted Cox regression analysis, HR = 1.62, 95%CI:1.06–2.47, p  = 0.021). Conclusion As most patients with EP-SCNC had a metastatic presentation, finding the primary tumor origin, which is important for patient prognoses, is both challenging and important at the same time. Only TTF-1 immunohistochemical analysis proved to be helpful with this task. Moreover, a diagnosis of primary lung small cell carcinoma cannot be established based on TTF-1 positivity, since only 25.7% of EP-SCNC in our study displayed TTF-1 positivity.

Preferentially expressed antigen of melanoma (PRAME) is a cancer/testis antigen selectively expressed in somatic tissues and various solid malignant tumors and is associated with poor prognostic outcome. Our research aimed to comprehensively compare its expression in a large cohort of tubo-ovarian epithelial tumors and examine its correlation with our clinico-pathologic data, as well as to assess its potential use in diagnostics and therapy.We examined 485 cases of epithelial tubo-ovarian tumors including 107 clear cell carcinomas (CCC), 52 endometroid carcinomas (EC), 103 high grade serous carcinomas (HGSC), 119 low grade serous carcinomas (LGSC)/micropapillary variant of serous borderline tumors (mSBT), and 104 cases of mucinous carcinomas (MC)/mucinous borderline tumors (MBT). The immunohistochemical analysis was performed using TMAs.The highest levels of expression were seen in EC (60%), HGSC (62%), and CCC (56%), while expression in LGSC/mSBT (4%) and MC/MBT (2%) was rare. The clinico-pathologic correlations and survival analysis showed no prognostic significance.The results of our study showed that PRAME is neither prognostic nor a suitable ancillary marker in the differential diagnosis of tubo-ovarian epithelial tumors. Nevertheless, knowledge about the PRAME expression may be important concerning its potential predictive significance, because targeting PRAME as a potential therapeutic option is currently under investigation.

Background Molecular aberrations occurring in primary ovarian clear cell carcinoma (OCCC) can be of diagnostic, predictive, and prognostic significance. However, a complex molecular study including genomic and transcriptomic analysis of large number of OCCC has been lacking. Methods 113 pathologically confirmed primary OCCCs were analyzed using capture DNA NGS (100 cases; 727 solid cancer related genes) and RNA-Seq (105 cases; 147 genes) in order to describe spectra and frequency of genomic and transcriptomic alterations, as well as their prognostic and predictive significance. Results The most frequent mutations were detected in genes ARID1A , PIK3CA , TERTp , KRAS , TP53 , ATM , PPP2R1A, NF1 , PTEN , and POLE (51,47,27,18,13,10,7,6,6, and 4%, respectively). TMB-High cases were detected in 9% of cases. Cases with POLE mut and/or MSI-High had better relapse-free survival. RNA-Seq revealed gene fusions in 14/105 (13%) cases, and heterogeneous expression pattern. The majority of gene fusions affected tyrosine kinase receptors (6/14; four of those were MET fusions) or DNA repair genes (2/14). Based on the mRNA expression pattern, a cluster of 12 OCCCs characterized by overexpression of tyrosine kinase receptors (TKRs) AKT3 , CTNNB1 , DDR2 , JAK2 , KIT , or PDGFRA (p < 0.00001) was identified. Conclusions The current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLE mut and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors.