Study reveals how aggressive breast cancer cells evade immune defenses

Study reveals how aggressive breast cancer cells evade immune defenses

With a new study in the journalScience BulletinResearchers at Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University have discovered a new way aggressive breast cancer cells evade immune defenses. This discovery also reveals a potential weakness that could make these tumors highly sensitive to existing immunotherapies.

It is known that many cancer cells have high levels of DNA damage and pieces of DNA can enter the cell's cytoplasm. This triggers an alarm system called the cGAS-STING pathway, which triggers an immune response to attack the tumor. However, researchers show that some tumors defend themselves with a specific molecule called FAM83H-AS1. This molecule acts like a switch and hijacks the body's alarm system. It changes the immune response from a strong anti-tumor attack to a state of chronic, pro-tumor inflammation. This shift helps the cancer establish an immunosuppressive tumor microenvironment that allows it to grow.

Crucially, this trick creates a major security hole. The same inflammatory process that protects the tumor also causes it to produce large amounts of a protein called PD-L1, an important drug target for cancer immunotherapy. Therefore, the tumors become highly susceptible to immunotherapy drugs designed to block PD-L1. Research shows that patients with tumors that overexpress FAM83H-AS1 could be ideal candidates for these existing treatments.

FAM83H-AS1 is a long noncoding RNA (lncRNA) located in chromosome 8q24, a region often associated with cancer risk but considered a “gene desert” because this large region contains very few protein-coding genes. Although the MYC oncogene is present in the environment, MYC expression is not altered in some tumors, which is not enough to explain the high risk of developing various tumors.

It is very likely that this region harbors important yet-to-be-discovered oncogenes.”

Man-Li Luo, principal investigator, professor and deputy director of the Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University

Although lncRNAs are more numerous in the human genome than protein-coding genes, their functions are often poorly understood, overshadowing their potential importance. An example is the lncRNA FAM83H-AS1. Despite clear evidence linking its overexpression to poor prognosis in a variety of cancers, the molecular machinery driving its role in tumor progression remains unclear.

The research team discovered that FAM83H-AS1 is often amplified and highly active in tumor tissues. High levels of this RNA molecule are associated with reduced antitumor immunity and poorer survival rates in breast cancer patients. What matters is that they explain how it works. Researchers reveal that FAM83H-AS1 hijacks a critical alarm pathway called cGAS-STING. Instead of triggering a strong anti-tumor interferon response, high concentrations of FAM83H-AS1 shift pathway signaling toward an NF-κB-driven pro-tumor inflammatory response. This switch effectively disables the body's natural defenses, turning immune attacks into cancer-causing inflammation.

These results demonstrate that FAM83H-AS1 is a key oncogene within the chromosome 8q24 region. The term “gene desert” refers only to protein-coding genes, but not to functional non-coding elements such as this central lncRNA. There are other “dark forests” of non-coding regulation waiting to be explored in the genomes.

Given that overexpression of FAM83H-AS1 is associated with poor prognosis in many cancers, the researchers believe that its immune evasion mechanism may not be limited to breast cancer. Their work also points directly to a therapeutic insight: tumors characterized by overexpression of FAM83H-AS1 or the resulting activation of NF-κB may be particularly susceptible to checkpoint blockade therapy.

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