Cancer cells are more involved in active combat with the immune system to its own survival. Opportunity to evade the immune system is a sign of cancer. Cancer cells produce biological "drones" to help these small vesicles called exosomes circulating in the blood and armed proteins called PD-L1, which cause the T cells to get tired before they can reach tumors and fight, according to researchers from the University Pennsylvania.
The work, published in the journal Nature, - a collaboration between Guo Wei, doctor of biological sciences at the School of Arts and Sciences, and Ksyauey Xu, MD, Professor of Pathology and Laboratory Medicine at the Medical School of Perelman. Mainly focused on metastatic melanoma, the team discovered that breast cancer and lung also release exosomes carrying PD-L1.
The study offers a paradigm-shift of the picture of how cancer is a systematic approach to the suppression of the immune system. In addition, it also points to a new way to predict which cancer patients will respond to the anti-PD1-therapy, which destroys the immune suppression to combat tumors and means of tracking the effectiveness of such treatments.
"Immunotherapy saved the lives of many patients with metastatic melanoma, but about 70 percent of these patients do not respond to treatment," - said Guo. "These treatments are expensive and have toxic side effects, so it would be very useful to know which patients will respond to treatment. Identification of a biomarker in the bloodstream could potentially help make early predictions about which patients will respond, and then you can offer them to the doctors to monitor how well their treatment is working. "
"Exosomes - a tiny encapsulated lipid vesicle diameter of less than 1/100 of a red blood cell. What we found with these circulating exosomes, really great "- Xu said. "We have collected blood samples from melanoma patients treated with anti-PD1-therapy.
One of the most successful innovations in cancer therapy is the use of checkpoint inhibitors are designed to block cancer cell attempts to suppress the immune system to tumor could thrive and proliferate. One of the main purposes of this class of drugs is the PD-1 protein on the surface of T cells. In tumor cells, they express the molecule analogue PD-L1, which interacts with PD-1 protein on T cells, effectively disabling the anti-cancer response that cell. Blocking this interaction using checkpoint inhibitors enhances T-cells, enabling them to unleash their tumor at the tumor of the tumor.
Although it has been known that cancer cells are transferred to PD-L1 on their surface, in this new work the team found that exosomes from human melanoma cells also carry a PD-L1 on their surface. Exosomal PD-L1 can directly bind to and block T cell function. Identification exosomal PD-L1, secreted by tumor cells provides a significant upgrade immune checkpoint mechanism and offers new insights into the immune evasion of tumor.
"Essentially exosomes secreted by melanoma cells, are immunosuppressive." Guo said. "We propose a model in which these exosomes act as drones to fight the T-cells in circulation even before the T cells close to the tumor." Since one tumor cell can secrete multiple copies of exosomes, the interaction between PD-L1 exosomes and T-cells provides a systematic and highly effective for suppressing anti-tumor immunity throughout the body. This may explain why cancer patients can weaken the immune system.
Since exosomes circulate in the bloodstream, they are available a method of monitoring cancer control / T cell through analysis of blood compared with conventional more invasive tumor biopsy. After the acute phase of treatment, researchers consider this test as a way to control how well the drug control cancer cells.
Measuring pretreatment levels of PD-L1, oncologists may be able to predict the extent of the tumor burden in a patient and link it with the result of the treatment. Furthermore, blood analysis can measure the effectiveness of the treatment, e.g., levels exosomal PD-L1 may indicate the level of T-cell activation inhibitors immune checkpoint.
"In the future I think we will start to think of cancers as a chronic disease, such as diabetes," - says Guo. "And in the same way as patients with diabetes use blood glucose meters to measure their level of sugar, it is possible that monitoring of PD-L1 and other biomarkers on circulating exosomes may be a way for doctors and cancer patients to follow the treatment. This is another step towards precision and personalized medicine. "