By using a new method to model ovarian cancer, researchers at Memorial Sloan-Kettering Cancer Center have gained new insights into the role of senescence in therapy response of high-grade serous ovarian cancers.

The study, co-corresponding author Josef Leibold told BioWorld Science, "will help us to gain insight into how we can re-sensitize tumor cells to immune surveillance mechanisms."

Since the approval of the first checkpoint blockade therapy, Yervoy (ipilimumab; Bristol Myers Squibb), in 2011, tumor immunotherapy has become a pillar of cancer treatment. Still, the approach is effective only in a minority of patients, and works much better in some tumor types than others. Finding ways to sensitize or re-sensitize the tumors to immune surveillance is a major area of research.

Leibold is a junior professor for functional immunogenomics at the University of Tubingen. The study will appear in the February 1, 2022, issue of the Proceedings of the National Academy of Sciences (PNAS) after earlier publication online.

Leibold, co-corresponding author Scott Lowe, first author Stella Paffenholz and their colleagues used electroporation to deliver plasmids with different combinations of genetic changes that are typical of ovarian cancer and its subtypes.

The investigators knocked out TP53 and activated MYC, as is almost universal in ovarian cancer patients, in all of their animals. They also compared animals with BRCA1 inactivation to those without.

"Using electroporation rather than classical genetically engineered mouse models to induce tumors has multiple advantages," Leibold said. "This electroporation approach is very elegant, if you think about the speed and the flexibility you have."

The plasmids are delivered directly to the ovaries, and the necessary surgery to expose the ovaries takes technical skills. But otherwise, "you need an electroporator and the plasmids, and you are good to go."

The method also reduces the number of animals and the time it takes to run a study. The method produces "cohorts big enough for preclinical studies, because the tumors come up synchronized," Leibold said. "And you can have tremendous genetic flexibility."

In germline models, "you have to breed and get a huge cohort of mice until you get the desired genotype," he added. "If you think about the 3R principles" -- a set of principles for the humane use of animals in research -- "and reducing extra animals, I think this is going to be the future."

Finally, the method could be used in larger animals as well, which are closer physiological models of humans, but cannot be used for breeding-based genetically engineered models because their generation span is far too long.

The uses of senescence

In the work now published in PNAS, the investigators showed that whether tumors responded to immunotherapy depended on whether the tumor cells went into senescence in response to platinum-based chemotherapy.

Furthermore, cells with BRCA deficiencies were far more likely to undergo senescence in response to chemo -- this was "the main difference between BRCA-proficient and BRCA-deficient cells," Leibold said.

Senescence is a two-part phenomenon. Senescent cells have stopped dividing, and they secrete multiple signaling molecules.

The problems that senescence can cause in aging organisms have received a lot of research attention in recent years.

But whether the phenomenon is beneficial or detrimental "is highly context-dependent," Leibold said. "If senescent cells persist, they have a lot of detrimental effects. But if you manage to acutely induce senescence in tumors and rewire the immune microenvironment in tumors, you might have beneficial effect."

In their experiments, the researchers demonstrated that the CCL5, CXCL10 and IL-6 secreted by senescent cells attracted T cells that in turn cleared the senescent cells.

Leibold said his team is looking at ways to clear senescent cells more rapidly after they have played their role in inducing a therapeutic response.

The scientists also plan to look at clinical data to see whether the mechanisms they have identified can be seen there as well.

Ultimately, the work advances the understanding of the genetics of who might respond to a given therapy. Such prediction remains much more art than science, because first CT scan to assess response is taken several months after therapy is started.

With most ovarian cancer cases still diagnosed late, that is time that patients do not have: the 5-year survival of those diagnosed with ovarian cancer is roughly 50%.