Purpose:In multiple oncological settings, expression of the co-inhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing co-inhibitory receptors such as PD-1, CTLA4, LAG-3 or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome amongst high-grade serous carcinoma (HGSC) patients remains controversial. Experimental Design: We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8⁺ T cells, CD20⁺ B cells, DC-LAMP⁺ dendritic cells as well as by PD-1⁺, CTLA4⁺, LAG-3⁺ and TIM-3⁺ cells in relation with prognosis and function orientation of the tumor microenvironment. Immunohistochemical data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. Results: High levels of PD-L1 and high densities of PD-1⁺ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust T_H1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1⁺TIM-3⁺CD8⁺ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, while PD-L1 levels and tumor infiltration by TIM-3⁺ cells improved patient stratification based on the intratumoral abundance of CD8⁺ T cells, the amount of PD-1⁺ cells failed to do so. Conclusion: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.

Purpose: The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937). Patients and Methods: We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC. Results: Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood. Conclusions: Our findings suggest that while patients with highly infiltrated, “hot” EOCs benefit from chemotherapy, women with “cold” EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.

Purpose: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. Experimental Design: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. Results: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. Conclusions: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10

Objective: To evaluate the safety, adequacy, and accuracy of tru-cut biopsy of gynaecologic tumours in a population of Czech women. Methods: A four-year retrospective study of ultrasound-guided tru-cut biopsy of gynaecologic tumours was conducted in the Department of Obstetrics and Gynaecology, Charles University, Hradec Kralove, Czech Republic. Results: One hundred and four women with gynaecologic tumours underwent transvaginal tru-cut biopsy within the study period. The most common indication for tru-cut biopsy in more than one-half of the women was a suspicion of malignancy/inability to exclude malignancy (59, 56.7%). Most of the tumours were malignant on histopathological examination (71, 68.3%), with advanced ovarian cancer being the most common type of malignancy (43/71, 60.6%). The overall adequacy and accuracy rates of tru-cut biopsy were 93.3% and 93.3%, respectively. Most of the inadequate samples were obtained from overweight and obese women (5/7, 71.4%), with only one biopsy sample taken in the majority of the inadequate biopsies (5/7, 71.4%). Accuracy was higher for malignant than benign tumours (97.7% vs. 82.4%). For malignant tumours, accuracy was highest for advanced ovarian cancers (33/40, 82.5%). Only one case was complicated by bleeding, giving an overall complication rate of 1%. The complicated biopsy was taken by a gynae-oncology trainee. Conclusions: Tru-cut biopsy is a cost-effective and safe preoperative diagnostic modality for patients with gynaecologic tumours, offering high adequacy and accuracy. It is particularly useful in patients with advanced ovarian cancer, most of whom present late with inoperable tumours that contraindicate primary surgery.

Supplementary Figure from An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors

Supplementary Figure from An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors