1. Kumar Das, Dibash PhD

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Ovarian cancer is generally advanced when it is diagnosed. At this late stage, symptoms may occur, but it is more difficult to treat and commonly fatal. The 5-year survival rate ranges from approximately 19 percent to 47 percent. High-grade serous ovarian cancer (HGSC) is the most common and the most malignant subtype, accounting for up to 70 percent of all ovarian cancer deaths. This underscores the need for differential treatment strategies for this clinical subgroup.

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HGSCs are deficient in the high-fidelity homologous recombination (HR) DNA repair pathway (HRwt), most commonly due to mutations of the BRCA1/2 genes. Consequently, these cells are dependent on error-prone DNA repair mechanisms. BRCA1/2 mutant (BRCA1/2 mut) tumors have been predicted to contain more neoantigens than tumors, with no alterations in genes of the HR pathway (HRwt).


Cancer immunotherapies, which boost the body's immune defense against cancer, have emerged as promising therapies in multiple tumor types. However, the effectiveness of immunotherapies against ovarian cancer has remained modest due to detailed understanding of the tumor-immune microenvironment (TME) in HGSC remaining unclear.


Now, researchers at the University of Helsinki have discovered how tumor cells interact with the immune system in ovarian cancer. The findings will help promote the development of prognostic and predictive biomarkers for HGSC (Nat Commun 2022;


The team aimed to investigate how tumor and immune cells communicate with each other to shape the genetic characteristics of HGSC. A single-cell analysis strategy was used to determine the cellular phenotypes and spatial differences in the TME landscapes of BRCA1/2 mut and HRwt tumors.


Utilizing a novel multiplex immunofluorescence and image analysis, the researchers generated and characterized spatial proteomic data for 21 markers in 124,623 single cells of the tumor, stromal, and immune cell populations in the TME of 44 HGSC patients. The 112 tumor cores were derived from 31 tumors with BRCA1/2 mutation and from 13 tumors without alterations in HR DNA repair.


Single-cell immunophenotyping revealed distinct divergent immune microenvironments between the immune subtypes and tumor and stromal metaclusters in tumors with BRCA1/2 mut as compared to the HRwt tumors. The distinct cellular subpopulations and their spatial interactions contributed to clinical outcomes in BRCA1/2 mut HGSCs. Investigation of the prognostic roles of the immunophenotypes revealed evidence of increased immunosurveillance capacity in the BRCA1/2 mut tumors.


The infiltration of CD8+ and CD4+ T cells correlated positively with the infiltration of various macrophages. Specifically, the BRCA1/2 mut tumors contained an increased infiltration of IBA1+ and M2-type IBA1+CD163+, and CD163+ macrophages. Moreover, the CD8+ T cells were typified by increased PD-1 expression in the BRCA1/2 mut tumors, suggesting potentially greater susceptibility to PD-1/PD-L1 targeted immune checkpoint therapies. In contrast, the lower CD8+ T-cell infiltration patterns reinforce the belief that T-cell exclusion is more frequent in the HRwt tumors.


Oncology Times reached out to Anniina Farkkila, MD, PhD, Associate Professor at the University of Helsinki in Finland, to learn additional insights on the study. Her research interest includes understanding the complexity and cell-cell interactions in the tumor microenvironment in ovarian cancer. She is a gynecologist and currently focuses on the treatment of gynecologic cancer patients at Helsinki University Hospital Department of Obstetrics and Gynecology.


Oncology Times: Why is genetic testing such a necessity for patients with HGSC?


Farkkila: "Genetic testing is critical in HGSC both for targeted treatments, such as with PARP inhibitors, and for revealing the potential inherited risk of cancer. Now, we found evidence that these mutations also contribute to how the tumors evade the immune system and shape the tumor microenvironment."


Oncology Times: What was the most compelling aspect of this study?


Farkkila: "Using a new imaging technology and advanced data analysis, we could investigate single cells in the tumors at an unprecedented resolution. We were able to analyze the functional properties and spatial interactions of over 120,000 single cells from 44 clinical HGSC samples. We found that the genetic mutations in the tumors define how the tumors hide from the immune system. Specifically, tumors with BRCA1/2 mutation induce more immune surveillance by the body's own killer T cells. By contrast, tumors without such mutations have more stromal cells that prevent the interaction of tumor and immune cells."


Oncology Times: What are the clinical implications of the study? How will the findings promote the tailoring of precision therapies for HGSCs?


Farkkila: "The findings implicate that tumors with BRCA1/2 mutation are more sensitive to immunotherapies that target T cells, such as immune checkpoint blockade. This also would mean that these tumors would likely benefit the most from combination therapies with, for example, PARP inhibitors and immunotherapies. By contrast, other approaches need to be developed for tumors without these mutations. For these tumors, we need to be able to increase the activity of the T cells and overcome the stromal barriers in the tumor microenvironment."


Oncology Times: What were some challenges you encountered and are there any follow-up investigations underway to strengthen some of the conclusions of this study?


Farkkila: "Under the recent years, several different highly multiplexed imaging technologies have emerged, but the challenge has been how to reliably extract biologically and clinically relevant information from these images. To address these challenges, we employed new tools to identify and annotate the single cells from the images. To further strengthen the findings, we are investigating one of the largest single-cell HGSC datasets, and also using functional profiling in immune-competent organoids to functionally verify the discovered precision oncology approaches."


Dibash Kumar Das is a contributing writer.