Cancer cells are more than a lump of cells growing out of control; they participate in active combat with the immune system for their own survival. Being able to evade the immune system is a hallmark of cancer. Cancer cells release biological "drones" to assist in that fight--small vesicles called exosomes circulating in the blood and armed with proteins called PD-L1 that cause T cells to tire before they have a chance to reach the tumor and do battle, according to researchers in the journal Nature. While primarily focused on metastatic melanoma, the team found that breast and lung cancer also release the PD-L1-carrying exosomes.
The research offers a paradigm-shifting picture of how cancers take a systemic approach to suppressing the immune system. In addition, it also points to a new way to predict which cancer patients will respond to anti-PD1 therapy that disrupts immune suppression to fight tumors and a means of tracking the effectiveness of such therapies.
"Immunotherapies are life-saving for many patients with metastatic melanoma, but about 70 percent of these patients don't respond," said the author. "These treatments are costly and have toxic side effects so it would be very helpful to know which patients are going to respond. Identification of a biomarker in the bloodstream could potentially help make early predictions about which patients will respond, and, later on, could offer patients and their doctors a way to monitor how well their treatment is working."
"Exosomes are tiny lipid-encapsulated vesicles with a diameter less than 1/100 of a red blood cell. What we have found with these circulating exosomes, is truly remarkable," said another author. "We collected blood samples from melanoma patients treated with anti-PD1 therapy. This type of liquid biopsy assay allows us to monitor tumor-related immune suppression with time. "
One of the most successful innovations in cancer therapy has been the use of checkpoint inhibitor drugs, which are designed to block attempts by cancer cells to suppress the immune system to allow tumors to thrive and spread. One of the primary targets for this class of drugs is PD-1, a protein on the surface of T cells. On tumor cells, they express a counterpart molecule called PD-L1, which interacts with the PD-1 protein on T cells, effectively turning off that cell's anti-cancer response. Blocking that interaction using checkpoint inhibitors reinvigorates T cells, allowing them to unleash their cancer-killing power on the tumor.
While it was known that cancer cells carried PD-L1 on their surface, in this new work, the team found that exosomes from human melanoma cells also carried PD-L1 on their surface. Exosomal PD-L1 can directly bind to and inhibit T cell functions. Identification of the exosomal PD-L1 secreted by tumor cells provides a major update to the immune checkpoint mechanism, and offers novel insight into tumor immune evasion.
"Essentially exosomes secreted by melanoma cells are immunosuppressive." Guo said. "We propose a model in which these exosomes act like drones to fight against T cells in circulation, even before the T cells get near to the tumor." Since a single tumor cell is able to secrete many copies of exosomes, the interaction between the PD-L1 exosomes and T cells provides a systemic and highly effective means to suppress anti-tumor immunity in the whole body. This may explain why cancer patients might have weakened immune system.
Because exosomes circulate in the bloodstream, they present an accessible way of monitoring the cancer/T cell battle through a blood test, compared to the traditional more-invasive biopsy of tumors. After an acute phase of treatment, the researchers envision such a test as a way to monitor how well the drugs are keeping cancer cells in check.
By measuring pre-treatment levels of PD-L1, oncologists may be able to predict the extent of tumor burden in a patient and associate that with treatment outcome. In addition, a blood test could measure the effectiveness of a treatment, for example, levels of exosomal PD-L1 could indicate the level of T cell invigoration by immune checkpoint inhibitors.
"In the future, I think we will begin to think about cancers as a chronic disease, like diabetes," says the author. "And just as diabetes patients use glucometers to measure their sugar levels, it's possible that monitoring PD-L1 and other biomarkers on the circulating exosomes could be a way for clinicians and cancer patients to keep tabs on the treatments. It's another step toward precision and personalized medicine."
https://www.pennmedicine.org/news/news-releases/2018/august/cancer-cells-send-out-drones-to-battle-immune-system-from-afar
https://www.nature.com/articles/s41586-018-0392-8
How tumors suppress immune system?
- 1,619 views
- Added
Edited
Latest News
Metabolic rewiring promotes…
By newseditor
Posted 18 Apr
A drug to prevent flu-induc…
By newseditor
Posted 18 Apr
New origin of deep brain waves
By newseditor
Posted 17 Apr
Starving cells hijack prote…
By newseditor
Posted 17 Apr
Miniature battery-free epid…
By newseditor
Posted 17 Apr
Other Top Stories
New method to target rheumatoid arthritis
Read more
Treating children with cerebral palsy
Read more
How different brain regions are connected
Read more
Treating epilepsy with a new on-demand and cell-autonomous gene the…
Read more
Mapping the path from smell to perception
Read more
Protocols
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Modular dual-color BiAD sen…
By newseditor
Posted 31 Mar
Publications
How does the microbiota con…
By newseditor
Posted 18 Apr
The integrated stress respo…
By newseditor
Posted 18 Apr
The immunobiology of herpes…
By newseditor
Posted 17 Apr
Circulating microbiome DNA…
By newseditor
Posted 17 Apr
Spindle oscillations in com…
By newseditor
Posted 17 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar