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A team of researchers at Memorial Sloan Kettering Cancer Center (MSK) has identified several immune escape mechanisms that could help explain why ovarian cancer has so far been resistant to immunotherapy
.
The researchers found that ovarian cancer is more complex than previously thought, with huge differences
in immune evasion between known genomic subtypes, and even between different tumors in the same patient.
They also learned that ovarian tumors create new mutations as they spread to evade the immune system
.
The study, published December 14, 2022 in the journal Nature, is the first study from a collaborative project called MSK SPECTRUM to focus on high-grade serous ovarian cancer
.
This type accounts for about 80% of all ovarian cancers and is the deadliest subtype
.
The immune system has a built-in braking system to prevent the body from reacting too strongly
.
The same checkpoint system can be exploited
by cancer cells that try to evade immune cells.
Immunotherapy drugs called checkpoint inhibitors remove the brakes on the immune system to attack cancer
.
They have successfully treated some advanced cancers
.
Dr.
Sohrab Shah, a computational oncologist and one of the two corresponding authors of the paper, said: "There is a lot of promise in clinical trials investigating checkpoint inhibitors in ovarian cancer, but the results are disappointing
.
" "We set out to find out why the immune system can't fight this cancer
the way it treats other diseases.
" What is the nature of the interaction between cancer cells and immune cells in ovarian cancer?"
"In this project, we studied pretreatment of ovarian cancer and used the latest tools to comprehensively characterize the interactions between tumor and immune cells," added
another corresponding author, medical oncologist and ovarian cancer expert Dmitriy Zamarin, M.
D.
"We performed several complementary analyses and integrated data to better understand how ovarian cancer manifests in patients and find answers
to the lack of response to immunotherapy.
"
The 42 patients who were recently diagnosed with advanced ovarian cancer who visited MSK's gynecologic oncology surgery clinic agreed to donate tissue
for the study.
All patients had high-grade serous ovarian cancer
.
In surgery to remove the tumor, researchers collect samples not only from the original tumor in the ovaries and fallopian tubes, but also from areas where the cancer has metastasized (spread) in the
patient's body.
This results in a total of 160 unique tumors to study
.
The team performed a "multimodal" analysis of patient samples, including:
Whole genome sequencing
Single-cell RNA sequencing, which allows researchers to identify genes
that are expressed or "turned on" in different cells, in different environments in the body in each cancer cell.
Understanding how cancer cells behave in their "microenvironment" (the collection of all the cell types that make up a tumor) is key
to understanding why immune cells don't recognize cancer cells.Multiplex immunofluorescence, a type of imaging that simultaneously identifies specific proteins and immune cell types in tissue samples
Digital pathology scan
Ovarian cancer is usually divided into different subtypes
based on their different genetic mutations.
One of the key findings is that the nature of immune recognition can be attributed to these genomic subtypes
.
This, in turn, may improve the individualized treatment
of patients.
But even within the same subtype, the researchers found that there could be profound differences between the tumors, suggesting they were more complex
than previously thought.
For example, some tumors in the same patient's body appear to be recognized by the immune system, while others remain hidden
.
"Ovarian tumors don't always respond to treatment as we expected, and this difference between different tumors in the same patient makes it challenging to identify a marker that can predict response to treatment," said
Dr.
Zamarin, who has led many clinical trials of the disease.
One of the big findings, reported in the paper, published in the journal Nature, is that as ovarian cancer grows and spreads, cancer cells develop new mutations to help them survive
.
Some of these mutations actually help tumors evade the immune system
.
Dr Shah said: "As cancer progresses, there is a cascading evolutionary arms race
.
The initial tumor seems to be recognized by the immune system, but later metastatic tumors that form at different anatomical sites acquire the ability to
evade immune recognition.
”
Dr Shah added that this finding makes it even more urgent to develop better early detection methods so that tumors can be eliminated before they
find a way to evade the immune system.
The study reveals a deeper explanation that doctors and scientists already know: ovarian cancer is extremely difficult to treat
.
But they say their work also reveals good news, pointing to possible new ways
to fight the disease.
Dr Zamarin said: "Now that we know some of the additional mechanisms that lead to treatment resistance, we have the opportunity to find better ways to improve treatment
.
The findings of this study give us many additional avenues to not only develop new treatments, but ultimately to better detection and prevention
.
”