A team led by researchers at MD Anderson Cancer Center reports a crucial tumor-thwarting gene protects an immune attack against lung cancer by blocking the key to an off switch on T cells, the customized warriors of the immune system. The study was published in the Journal of the National Cancer Institute.
“Identifying this role for tumor-suppressing p53 provides both a potential biomarker for response to important new cancer immunotherapy drugs and a possible new therapeutic pathway for treatment,” said James Welsh, M.D., associate professor of Radiation Oncology at MD Anderson and senior author.
This preclinical research shows an experimental drug currently in phase I clinical trials can replace the immunity-protecting role lost when p53 fails.
The p53 gene is damaged, missing or under-expressed in 42% of common cancers and 70% of lung cancers. It’s by far the most common mutation in cancer. Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute.
Scientists have long known that p53 plays a central role in cancer control by regulating a process that forces abnormal cells to repair themselves and, failing that, to kill themselves.
Welsh and colleagues found that p53 also blocks a protein called PDL1 that tumor cells can wield to halt immune attack. Like a key, PDL1 connects with and activates a checkpoint molecule called PD1 found on the surface of T cells that shuts down those killer white blood cells. Two PD1-inhibiting drugs, pembrolizumab (Keytruda) and nivolumab (Opdivo) were approved this year for treatment of metastatic lung cancer. Both drugs help a significant fraction of patients, but not all.
p53 launches miR-34a to thwart PDL1
First author Maria Angelica Cortez, Ph.D., instructor of Experimental Radiation Oncology, identified the mechanism by which p53 blocks expression of PDL1.
“The interaction is specific: p53 activates the micro RNA miR-34a, which in turn directly blocks expression of PDL1,” said Cortez. “If you lose p53 function, then miR-34a is lost and PDL1 is over-expressed.”
Unlike messenger RNAs produced by genes that lead to production of specific proteins, micro RNAs do not code for proteins, they regulate other genes.
While p53 had been linked to other aspects of immune response, the JNCI paper is the first to connect it to immune evasion by tumors and regulation of PDL1.