Cancer cells survive in the body because they’re able to hide from the immune system, evading the cancer-fighting T cells on constant patrol.
These cancer cells become “immune-silent,” said Judith Agudo, PhD, a principal investigator at Dana-Farber Cancer Institute, Boston, Massachusetts, and immunology professor at Harvard. “They repress key genes that call in, and allow for recognition by, immune cells; so, they become super quiet.”
For more than two decades, scientists have been investigating the tactics behind this “immune evasion,” part of cancer’s immunoediting strategy. Research in this area has been crucial in paving the way for immunotherapy, a flourishing field in oncology that has already changed the treatment of some solid cancers.
Adding to scientists’ growing understanding is a new Nature study, coled by Agudo, detailing a potential new mechanism for how early colorectal cancer cells evade immune detection.
“We’ve known that immune evasion is important in advanced cancers and in metastatic cancers,” said the other colead author, Omer Yilmaz, MD, PhD, a cancer researcher at Massachusetts Institute of Technology and gastrointestinal pathologist at Massachusetts General Hospital in Boston, Massachusetts. “But we knew much less about the role of [immune evasion] in early cancers.”
How Early Cancer Cells May Hide
The researchers implanted mice with cells genetically engineered to have three gene mutations common in colorectal cancer: Apc, Kras, and Trp53.
Using a technique called ATAC-seq, they identified areas of the genome where the DNA is loosely packed and accessible — that is, areas where various mechanisms (like transcription factors) control gene expression. Within these regions, they performed motif analysis, searching for short DNA sequences (motifs) and identifying their role.
What they found intrigued them: High levels of motifs recognized by the SOX family of transcription factors.
Further analysis revealed a transcription factor called SOX17 as key in the cancer’s development. SOX17 is a fetal transcription factor, which plays a crucial role in fetal development.
“One paramount role for SOX17 is specification of the intestine during embryogenesis,” Yilmaz said.
Like cancer cells, fetal tissues are immune-silent, Agudo said, so that the mother’s immune system won’t attack them.
More Clues
The researchers edited the cells to knock out SOX17 and performed their experiments again. This time, only 6% of the cells became cancerous, compared with 80% with SOX17 present.
They also observed an increase in the number of T cells recruited to fight the tumors. Analyzing those T cells revealed a clue that interferon-γ (IFNγ) might be involved.
“Every single cell in the body has an interferon-γ receptor,” explained Agudo. When IFNγ binds to the receptor, the cells respond by releasing chemokines that call in more T cells and increase antigen presentation so the T cells can recognize the potential threat.
“SOX17 binds to the promoter of the receptor, and it actually diminishes the expression of the receptor a lot,” Agudo explained. “With very little receptor, the cell cannot respond to IFNγ.” In tumors with SOX17, the IFNγ pathway was downregulated, RNA sequencing confirmed.
Previous research has found that IFNγ can be downregulated in treatment-resistant cancers. However, this is the first evidence that the IFNγ pathway may be controlled independently of spontaneous gene mutations, Agudo said.
The researchers also looked at human biopsies and found that SOX17 was active in 100% of precancerous polyps and 70% of colon cancer samples, dovetailing with the theory that SOX17 is important in colorectal cancer’s early stages.
How does a fetal transcription factor turn on in the first place? “That’s the one mystery we don’t quite understand,” Yilmaz said. “That’s an area of future active investigation.”
In Practice: How Could This Affect the Future of Cancer Treatment?
More research is needed to confirm the study’s findings, but if the mechanism holds up, it could lead to new treatments.
If we could find a way to block SOX17 activity, we could prevent “early polyps from becoming cancers and early-stage cancers from developing into later-stage cancers,” said Anvi Desai, MD, a gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center in Commack, New York. (Desai was not involved in the study.)
However, identifying and testing a drug like that would take time — this study is just the beginning of that process, Desai said.
Still, Agudo and Yilmaz are optimistic. They hope to identify proteins that interact with SOX17 and target them with small molecules or other approaches to help diminish SOX17 activity. “We’re far away from exploiting this with inpatients therapeutically,” Yilmaz said, but “it’s a new mechanism, and we’re going to delve deep into it.”
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