At the 2023 Society of Gynecological Oncology’s Annual Meeting on Women’s Cancer in Tampa, Florida, Aaron Praiss, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses the role surgical stress may play in promoting IL-6–driven tumor progression in high-grade serous ovarian cancer.

Dr Praiss shared results from a study which found that mice who underwent laparotomy had significant increased IL-6 concentration from baseline, compared to those who did not undergo laparotomy.

Transcript

Hi, I'm Aaron Praiss. I'm a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center in New York City. And I'm here at the 2023 SGO Annual Meeting on Women’s Cancer in Tampa, Florida today presenting my research with Dr Dmitriy Zamarin on how surgical stress potentially would increase tumorigenesis in an ovarian cancer mouse model.

After looking at a human model of patients undergoing primary cytoreductive surgery with high-grade serous ovarian cancer, where we saw intratumoral evolution of upregulation of IL-6 in RNA sequencing, as well as IL-6, the cytokine in peripheral serum blood, we decided to target this in an ovarian cancer novel mouse model. We injected all our 6- to 8-week-old female mice with a novel ovarian cancer model that was created at Memorial Sloan Kettering Cancer Center that's BRCA1- and TP53-mutated and tagged with luciferase so that we could do bioluminescence imaging.

I then did an intervention of a laparotomy or no laparotomy, which was designed to create surgical stress in the mice. Half the mice received a laparotomy, and half the mice did not. Around this time, 24-hours pre-op and 24-hours post-op, we obtained retro-orbital blood to look at their serum IL-6 blood levels. Following this, we performed injections intraperitoneally of 2 experimental arms, one an anti-IL-6 cytokine receptor antibody or an anti-IgG control. This was injected 24-hours pre-op, 24-hours post-op, and then weekly for 2 weeks. All the mice were followed with twice-weekly bioluminescence imaging after their intervention to assess tumorigenesis. A subset of mice was also euthanized about 2 weeks after the injection of their cell line for flow cytometry analyses of their tumors.

Overall, in terms of results in their blood, we saw similar results to what we saw in our humans. The IL-6 concentration is significantly increased in the mice 24 hours post-op who underwent laparotomy. And the mice who did not undergo laparotomy, this was the same value before and after. For their flow cytometry analyses, the percent of natural killer cells expressing granzyme B were decreased in the tumors of the laparotomy mice demonstrating immune dysfunction in these tumors postoperatively. Then the CD4 and CD8 cell counts with PD-1 expression were increased in both cell populations of the laparotomy mice, also indicating immune dysfunction postoperatively.

In terms of bioluminescence imaging between our experimental arms, the mice that underwent laparotomy with anti-IgG control intraperitoneal injections had the most tumor growth based on bioluminescence imaging compared to the mice that underwent laparotomy but received the anti-IL-6 receptor antibody treatment intraperitoneally, suggesting that the anti-IL-6 receptor treatment potentially is ameliorating some of this IL-6 driven surgical stress tumorigenesis post-op. Additionally, our results showed that the mice that did not undergo laparotomy had much less tumorigenesis compared to both experimental arms that did undergo laparotomy. In the mice that did not undergo laparotomy, anti-IL-6 treatment had no effect. It was the same tumorigenesis for the anti-IL-6 and anti IgG treated mice.

All of this together is exciting hypothesis-generating work that shows IL-6 is a part of the cytokine cascade that's happening post-op in these laparotomy mice, or the patients undergoing large cytoreductive surgeries for ovarian cancer. It's probably not the only thing, but this is exciting to see that even blocking just IL-6 in these mice is delaying some of this tumor growth and would be an exciting next step to assess further in translational research or in human models at some point.

Source:

Praiss A. “Surgical stress promotes IL-6–driven tumor progression in ovarian cancer.” Presented at: SGO Annual Meeting on Women's Cancer; March 25-28, 2023; Tampa, FL