LIMIT Found to Be Cancer Immunogenic lncRNA

A long noncoding RNA whose function was previously unknown turns out to play an important role in promoting the body's immune response against cancer and holds promise for enhancing the efficacy of anti-cancer immunotherapy—according to new findings reported in Nature Cell Biology. The study was led by researchers at the University of Michigan. The group dubbed the RNA they identified LIMIT—for long noncoding RNA inducing major histocompatibility complex class I and immunogenicity of tumor.

"LIMIT is easy to remember, but really it does the opposite. It stimulates immune functions against cancer," says senior study author Weiping Zou. LncRNAs are known to play some important roles in cancer, but very little is known about their roles in the context of the immune system's response to cancer, Zou says. "LncRNAs have mainly been studied in cancer models that lack a functioning immune system, leaving a big gap in our knowledge," adds study first author Gaopeng Li. "When it works, immunotherapy can be amazingly successful, but doesn't work in more than half of patients. We wanted to better understand what role lncRNAs play and whether there might be opportunities to target them to improve immunotherapy."

After confirming that LIMIT was indeed a long noncoding RNA, the researchers conducted experiments in human tumor cells and mouse cells to better understand its function, explains Zou. And it turns out that LIMIT is regulated by interferon gamma, a cytokine that plays a central role in the body's ability to mount an immune response against an invading threat. Subsequent experiments in mice showed that LIMIT is a vital component of T cell infiltration into tumors.

"If you get rid of this lncRNA, the mice are much less able to fight off the cancer," Zou says. "The T cells don't go to the tumor and they don't function normally." Ultimately, the research determined that LIMIT activates a family of genes known as GPBs (for guanylate binding proteins), leading to the activation of other important immune players: heat shock factor-1 (HSF1) and major histocompatibility complex class I (MHC-I).