OCRA-Funded Research Sheds Light On Ovarian Cancer Resistance to Immunotherapy

As immunotherapies have seen rising success in treating several other cancers, researchers are hard at work uncovering why immunotherapy for ovarian cancer has, so far, proven ineffective. 

In a study published in Nature, a research team at Memorial Sloan Kettering Cancer Center set out to identify specific factors that lead to immune evasion in high-grade serous cancer (HGSC). (Because this study focuses on fallopian tube lesions outside the ovaries, it references HGSC rather than HGSOC.) The study, funded in part by OCRA, was led by Dr. Sohrab Shah and Dr. Dmitriy Zamarin, both OCRA grantees, and included OCRA grantees Dr. Rachel Grisham and Dr. Ignacio Vazquez-Garcia. This is the first study performed by MSK SPECTRUM, a scientific collaboration focused on HGSC.

HGSC is recognized by scientists as having distinct mutational processes, as well as significant differences in genetic makeup and behavior of cancer cells, even within the same patient. Results from this study shed more light on these complexities, in particular revealing that ovarian tumors develop additional mutations in order to evade the immune system.

Immunotherapy drugs called “checkpoint inhibitors” have proven effective in treating some cancers by deactivating the body’s natural “checkpoints” to suppress immune response, which are triggered when the body senses that a high immune response may overwhelm the system. By inhibiting these immune checkpoints, and allowing the immune system to keep working, immune cells can then fight against the cancer cells. Disappointingly, prior clinical trials have shown that checkpoint inhibitors are not effective at stimulating immune response against ovarian cancer.

To find out more, researchers in this study performed analysis on tumors from 42 patients. All patients participating in the study were recently diagnosed with HGSC, were being treated at MSK, and agreed to donate tissue for research. Tumors were collected from the ovaries and fallopian tubes, as well as from sites of metastasis, resulting in a total of 160 tumors for analysis.

The team performed a multimodal analysis, using a variety of methods including whole gene sequencing, digital pathology scans, multiplexed immunofluorescence (imaging that identifies proteins and immune cells), and single-cell RNA sequencing. Single-cell RNA sequencing allows researchers to see which genes are being expressed (turned on, or activated) in cancer cells throughout the body. Learning how cancer cells behave in different microenvironments is important to better understand what keeps immune cells from recognizing cancer cells. 

Their results suggest that ovarian tumors may be even more complex than previously thought, finding that ovarian tumors differ significantly in their makeup and behavior even when the tumors are from the same patient. Importantly, in some cases, they found that even if one tumor is recognized by the immune system, others from the same patient can evade immune system recognition.

In addition, the team made a significant discovery about why this may be the case. They found that as ovarian tumors develop, they can produce new genetic mutations that allow the cancer cells to survive, including mutations that allow them to “hide” from the immune system.

In a press release from MSK, Dr. Shah said, “There’s a kind of cascading evolutionary arms race that happens as the cancer progresses. The original tumors appear to be recognized by the immune system, but metastatic tumors formed later, in different anatomic sites, acquire the ability to evade immune recognition.”

While the results offer a deeper understanding into the challenges of treating HGSC, they also provide hope, and potential areas of promise for future breakthroughs.

“Now that we know some of the additional mechanisms that are driving resistance to therapy, we have an opportunity to find better ways to improve treatments,” said Dr. Zamarin in the press release. “The findings from this study have given us many additional avenues to pursue, not only for developing new treatments but, ultimately, also better methods for both detection and prevention.”

Read more about “Ovarian cancer mutational processes drive site-specific immune evasion” in Nature, and in a press release from Memorial Sloan Kettering Cancer Center.

Dr. Shah’s Collaborative Research Development Grant was supported in part by a generous donation from Ovarian Cycle New York.

Dr. Zamarin’s Early Career Investigator Grant was supported in part by a generous donation from Torrid.