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Unraveling how DNA repair mutations drive cellular changes in ovarian cancer to improve patient outcomes

See how a team of researchers at Cedars-Sinai Medical Center in Los Angeles, CA are probing the biology of ovarian cancer using the latest spatial biology technologies and paving the way for better patient outcomes for this devastating disease.

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Ovarian cancer, while rare compared to other forms of cancer, is one of the deadliest that can occur in women. It’s an aggressive disease which is typically diagnosed at a late stage (due to a lack of reliable early detection biomarkers) and often develops drug resistance, characterized by repeated cycles of remission and recurrence.

In the United States alone, the National Cancer Institute (NCI) estimates that there were 19,710 new cases and 13,270 deaths from ovarian cancer in 2023, with a 5-year survival rate of only 50.8%. Imagine that – your mother, sister, friend, neighbor, or colleague being diagnosed with a disease where the odds of being cured are equivalent to that of a coin toss.

However, researchers in the Jones Lab at Cedars Sinai Medical Center in Los Angeles, CA, led by Michelle Jones, PhD, are starting to uncover vital clues in the immune landscape of cancer tissues that may offer hope for more effective therapeutic strategies.

Taking a comprehensive spatial biology approach

The Jones Lab takes a multiomic approach to studying ovarian cancer – analyzing the genome, transcriptome, methylome, and proteome in conjunction to get the most comprehensive view of the disease.

Looking at upstream data from high-grade serous ovarian cancer (HGSOC) patient samples, the researchers found that some of the genetic changes in the tumors, like homologous recombination deficiency, were associated with notable changes in the immune landscape of the tumors. This inspired them to dive deeper into the HGSOC tumor microenvironment with advanced spatial proteomics analysis – phenotyping whole tissues at single-cell resolution, mapping how immune and tumor cells are organized, and exploring how their interactions impact treatment response and disease progression.

As Kruttika Dabke, PhD, a postdoc in the Jones Lab, discussed in her SITC (Society for Immunotherapy in Cancer) 2023 poster presentation (6-minute video), the team used a 26-plex antibody panel on the PhenoCycler-Fusion platform to profile millions of cells from 23 patient samples and get a fresh perspective on the disease’s biology. The panel included markers for obtaining a rich view into different immune cell populations (like M1 vs M2 macrophages, four different types of T cells, NK cells, and more), tumor cells, fibroblasts, and smooth muscle. Continue reading to see what they discovered in the HGSOC tumor microenvironment, how it is rearranged after treatment, the effect of homologous recombination repair (HRR) mutations, and the therapeutic implications.

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Focusing on DNA Repair pathway mutations

Defective DNA repair is a hallmark of cancer. This deficiency in the homologous recombination repair (HRR) pathway that acts on DNA double-strand breaks has been termed homologous recombination deficiency (HRD).

Tumors that are not HRD are considered homologous recombination proficient (HRP) and contain no functional genetic alterations in HR pathway genes, like BRCA1/2, resulting in faithful DNA repair, thereby reducing the mutation burden.

Why does this matter? The presence of HRD can make ovarian cancers more sensitive to some platinum-based chemotherapies and PARP inhibitors, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. So, identifying the HR status of patients could help align them with the right therapy. Clinicaltrials.gov lists more than 200 active studies of PARP inhibitors as of today. So, this is a significant therapeutic area that warrants further research.

Tracing immune cells and other tumor activity with spatial proteomics

The Cedars-Sinai team wanted to investigate how exactly homologous recombination status influences the immune landscape in these tumors. They started by profiling the proteome, genome, and transcriptome of both chemo-naive (or primary) and chemo-resistant (or recurrent) HGSOC tumors.

They then used this data to create a customized multiplex antibody assay on the PhenoCycler-Fusion platform which was applied to 23 tissue sections, and they were able to identify and characterize an average of 1.5 million cells per section.

Kruttika Dabke SITC 2023 Poster Figure 1

“The great advantage of using Akoya Biosciences was to be able to stain the entire section of tissue and not be restricted to regions of interest (ROIs), which are usually what other spatial technologies use,” Dr. Dabke said.

A look at the relative abundance of different cell types immediately showed differences between HRD and HRP samples, with significantly higher proportions of M1 macrophages in the HRD group compared to the HRP group within the primary tumors, and a higher proportion of Regulatory T cells (Tregs) within the recurrent tumors.

Kruttika Dabke SITC 2023 Poster Figure 2

Delving deeper, the team identified 15 spatial neighborhoods characterized by their unique cell type compositions.

Kruttika Dabke SITC 2023 Poster Figure 3

Recurrent tumors were observed to have remarkably lower proportions of CN9 (cells interacting with Helper T cells) in the HRD compared to the HRP group, and higher proportions of CN14 and CN15 (cell interacting with B cells) compared to the primary tumors.

Spatial proximity analysis revealed even more about how the HGSOC tumors respond to chemotherapy.

Kruttika Dabke SITC 2023 Poster Figure 4

Dr. Dabke said there were significant differences between the proximity of different immune cells to each other within the HRD tumors and HRP tumors, especially in the primary (chemo-naive) tumor group.

“But as soon as these tumors received chemotherapy and we looked at the recurrent tumors, that difference in cellular localization disappeared,” she added. “This is telling us that the spatial organization of these immune cells is really changing in response to chemotherapy in these patients.”

This study, presented in a poster at SITC 2023, demonstrates the advantages of single-cell spatial phenotyping enabled by the PhenoCycler-Fusion system to reveal significant spatial organizational differences that could not be discerned by merely counting cells without knowing their specific locations within the tissue.

“It really gave us a deeper understanding of how immune cells reorganize themselves in response to chemotherapy or homologous recombination deficiency,” she said.

Spatial proximity analysis revealed even more about how the HGSOC tumors respond to chemotherapy.

A glimpse into future possibilities

This was the Cedars-Sinai team’s first experience with the PhenoCycler-Fusion platform, and the researchers are still parsing through the wealth of information provided by the spatial experiment. They are now considering adding more samples to profile even more primary and recurrent tumors as well as pairs of two tumor samples from different patients.

Ultimately the goal is to turn these spatial insights into reliable biomarkers that help stratify patients into responders (those who can benefit from immunotherapy) and non-responders, and even to tailor new precision medicine therapies to each individual’s specific biological profile.

To that end, one pioneering biopharma company, Acrivon Therapeutics, is already zooming ahead. Click here to read about the Acrivon ACR-368 OncoSignature test for ovarian cancer, which was granted FDA breakthrough device designation in 2023, and see what that future is shaping up to look like.

Resources recap:

  • Watch Dr. Kruttika Dabke’s SITC 2023 poster presentation (6-minute video).
  • Download Dr. Kruttika Dabke’s SITC 2023 poster (PDF).
  • Read about the Acrivon ACR-368 OncoSignature test for ovarian cancer.
  • Connect with us if you’d like to discuss how Akoya’s spatial biology solutions can help you advance your research.

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