Posted on May 30, 2019, 4 p.m.
RNA molecules were once thought to do their work inside cells, but it has become clear that RNA molecules are also active outside of the cell, with potentially major implications for health. NIH launched the Extracellular RNA Communication Program roughly 5 years ago to investigate unrecognized roles such as these.
Recently researchers described progress in defining the secrets of exRNA in 18 reports published in the Cell family of journals, but it is not just RNA they are studying they are also studying proteins. Among the exciting results is the discovery that proteins carried inside exosomes may influence cancer’s response to immunotherapy, which may help explain why certains cancers are resistant to immunotherapy and opens the door to new strategies in the fight against cancer.
Checkpoint inhibitor immunotherapy drugs are involved in their findings, which are monoclonal antibodies that can boost the ability of the immune system to attack and treat cancer. One of these specifically targets PD-1 protein on the surface of certain immune cells; when PD-1 binds with PD-L1 protein on the surface of another cell the interaction prevents immune cells from attacking, some tumours have developed this ability and load up on PD-L1 to evade the immune system. Checkpoint inhibitors block interactions between PD-1 and PD-L1 to allow certain immune cells to activate and attack the tumor.
Checkpoint inhibitors works better in some cancers than others, in melanoma for instance 30% of patients respond to this therapy but rates are in the single digits in prostate cancer. To investigate why researchers from the University of California looked at RNA within cells taken from immunotherapy resistant prostate cancers, findings are published Cell.
PD-L1 protein was present in the resistant cancers as expected, but the PD-L1 messenger RNAs revealed unexpected data, resistant cancer cells made more PD-L1 mRNAs than needed to produce levels of PD-L1 proteins detected inside the cells. The missing PD-L1 was found in exosomes; cancer cells packed large quantities of the protein inside exosomes and were secreting them out of the cell to other parts of the body.
In mouse models of prostate cancer those packed exosomes were found traveling through the blood and lymphatic systems to lymph nodes, once there laden exosomes put the immune system to sleep which prevented certain cells from locating and attacking the cancer.
Two genes in cancer cells were edited to prevent them from producing exosomes, in the absence of exosomes the cells no longer formed tumours. Edited and unedited cells still produced PD-L1, but only those exporting PD-L1 in exosomes deactivated the immune system, similar results were yielded in mouse models of immunotherapy resistant colorectal cancer.
Blocking release of PD-L1 in exosomes, even temporarily, may allow the immune system to activate and launch an effective and sustained attack against cancer. While it is not clear why antibodies that target PD-L1 on cancer cells but they do not disable on PD-L1 found in exosome, findings suggest it may be possible to find a small molecule to target PD-L1 laden exosomes to unleash the immune system against checkpoint inhibitor resistant cancers.
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