Study uncovers how aggressive breast cancer cells escape immune defenses

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

It has been known that many cancer cells have high levels of DNA damage, and bits of DNA can leak into the cell cytoplasm. This triggers an alarm system called the cGAS-STING pathway, which induces an immune response to attack the tumor. However, researchers show that some tumors fight back using a specific molecule called FAM83H-AS1. This molecule acts like a switch, hijacking the body's alarm system. It changes the immune response from a potent anti-tumor attack to a state of chronic, pro-tumor inflammation. This shift helps the cancer build an immunosuppressive tumor microenvironment, allowing it to grow.

Crucially, this trick creates a major vulnerability. The same inflammatory process that protects the tumor also causes it to produce high levels of a protein called PD-L1, a key drug target for cancer immunotherapy. Therefore, the tumors become highly susceptible to immunotherapy drugs designed to block PD-L1. The research indicates that patients with tumors overexpressing 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 linked to cancer risk-but deemed a "gene desert", because this large region contains very few protein-coding genes. Although the MYC oncogene is present in the vicinity, MYC expression is not altered in some tumors, which is insufficient 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, study principal investigator, Professor and Deputy Director of Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University

While lncRNAs vastly outnumber protein-coding genes in the human genome, their functions are often poorly understood, overshadowing their potential significance. An example is the lncRNA FAM83H-AS1. Despite clear evidence linking its overexpression to poor prognosis in a wide range of cancers, the molecular machinery driving its role in tumor progression has remained elusive.

The team of researchers discovered that FAM83H-AS1 is frequently amplified and highly active in tumor tissues. High levels of this RNA molecule are linked to reduced anti-tumor immunity and poorer survival rates in breast cancer patients. Crucially, they elucidate how it works. Researchers reveal that FAM83H-AS1 hijacks a critical alarm pathway known as cGAS-STING. Instead of triggering a potent anti-tumor interferon response, high levels of FAM83H-AS1 shift the pathway's signaling toward an NF-κB-driven pro-tumor inflammatory response. This switch effectively disarming body's natural defenses, turning immune attacks into cancer-fueling inflammation.

These findings establish FAM83H-AS1 as a key oncogene within the chromosome 8q24 region. The term "gene desert" is a desert only for protein-coding genes, not for functional non-coding elements like this pivotal lncRNA. There are more "dark forests" of non-coding regulation waiting to be explored in the genomes.

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