Researchers have uncovered how tumor cells interact with the immune system in ovarian cancer. Utilizing highly multiplex immunofluorescence and image analysis, they investigated how the genetic characteristics of ovarian cancer shape how tumor and immune cells communicate with each other. More specifically, how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment.

This work is published in Nature Communications in the paper, “Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer.

“With the help of this revolutionary imaging technology and advanced data analysis, we were able to study individual tumor cells, their functional properties, and interactions with unprecedented precision,” said Anniina Färkkilä, MD, PhD, principal investigator at Helsinki University.

The team noted that they generated spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation, and from 13 tumors without alterations in homologous recombination (HR) DNA repair. They noted that the majority of high-grade serous ovarian cancers (HGSCs) are deficient in HR DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes.

“By studying individual cells directly in the tissue, we demonstrated how cancer cells hide in different ways, depending on the specific gene mutation,” said Inga-Maria Launonen, a graduate student in the Färkkilä lab. “We found that the body’s immune system is more effective against tumors with a mutation in BRCA1/2 genes. By contrast, tumors without such mutations have a connective tissue barrier prohibiting the interaction between the cancer and immune cells.”

Every year, roughly 550 women develop ovarian cancer in Finland. Ovarian cancer is difficult to treat and is commonly fatal, with 320 women dying of ovarian cancer annually in Finland. BRCA1/2 mutations occur in approximately 20% of poorly differentiated serous carcinomas, the most common form of ovarian cancer. The killer T cells closely guarded the aggressive tumor cells particularly in tumors with BRCA1/2 mutations, which is why these patients had a markedly better prognosis.

This work, the authors noted, identified a phenotypically distinct tumor microenvironment in the BRCA1/2 mutation tumors with evidence of increased immunosurveillance. Importantly, they noted, “We report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T cells in the BRCA1/2 mutation tumors.”

“By increasing our understanding of how tumor genes trick the immune system, we will be able to develop more effective ways to activate the body’s own immune defenses to kill the cancer cells,” Launonen said.

The results of the study confirm the significance of the interaction between tumor and immune cells in identifying new and more effective therapies as well as in choosing the right therapy for each patient.

“Our findings will enable us to tailor precision immuno- and combination therapies that have the potential to even cure ovarian cancer in the future,” Färkkilä said.

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