Cancer-Causing Mutations Also Boost Tumor Immunoresistance

Mutations in the Ras gene are double trouble. Not only do they drive 25% of human cancers, they also suppress the immune system’s anticancer response. Essentially, these mutations turn good cells bad, and they also help bad cells masquerade as good cells by boosting the expression of a protein called PD-L1, or programmed death-ligand 1.

PD-L1, which is ordinarily expressed in small amounts in the body, serves to prevent the immune system from attacking healthy cells. However, PD-L1 can also be expressed by cancer cells, which use the protein, a so-called checkpoint inhibitor, to avoid coming to the immune system’s attention.

Although PD-L1 is being targeted by cancer immunotherapies, which try to unmask cancer cells, much about PD-L1 remains unknown. For example, PD-L1 regulatory mechanisms remain unclear. If these mechanisms were better understood, they could, perhaps, be obstructed by new drugs, which could bolster existing cancer immunotherapies, which show promise but still deliver only mixed results.

PD-L1 expression, researchers at the Francis Crick Institute have just reported, can be upregulated by oncogenic RAS signaling. This mechanism involves increases in PD-L1 mRNA stability via modulation of the protein tristetraprolin (TTP), which binds AU-rich elements (AREs). Additional details appeared December 12 in the journal Immunity, in an article entitled “Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA.”

“TTP negatively regulates PD-L1 expression through AU-rich elements in the 3′ UTR [untranslated region] of PD-L1 mRNA,” wrote the article’s authors. “MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2.”

As part of the study, mice with Ras mutant cancers were given compounds to counteract the effects of Ras signaling on PD-L1 expression. Their tumors were attacked by the immune system, slowing tumor growth.

“In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA,” the authors explained. “We demonstrate that RAS can drive cell-intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RASmutant cancers.”

By revealing the causal link between Ras and PD-L1 levels, and the mechanisms behind it, the new study offers new possibilities for combination therapies using different drugs.

“Understanding how different mutations protect cancer cells from the immune system will help us to offer patients more precise and effective treatments,” commented Matthew Coelho, Ph.D., a researcher at the Francis Crick Institute and the first author of the current study. “Antibodies that target PD-L1 proteins are currently used in the clinic, and they work very well in around a fifth of lung cancer patients. At the moment, doctors can measure PD-L1 levels to help determine which patients might respond best, but this only gives you half of the story.

“For cancer immunotherapies targeting PD-L1 to work, you need two things: First, you need PD-L1 to be blocking immune attack in the patient’s tumor. Second, the immune system is only able to recognize and attack cancer cells that produce ‘antigens,’ molecules that immune cells can bind to. Cancer antigens are currently difficult to test for clinically, so PD-L1 is now a major test for deciding if immunotherapy will work. It is therefore very important to understand what turns on PD-L1 in cancer.”

“Our study highlights the fundamental role that Ras mutations play throughout the different stages of cancer,” added senior author Julian Downward, Ph.D., group leader at the Francis Crick Institute and head of the Lung Cancer Group at the Institute of Cancer Research (ICR). “We already knew that they played a key role in starting around a quarter of all human cancers, causing cancer cells to grow, multiply, and spread. We now know that they also help to protect the cancer cells from our immune systems, making them more difficult to treat. Understanding the mechanisms behind this will help us to develop better treatments in future, for example, boosting immunotherapy approaches with drugs that disrupt cancer’s defenses.”