New Mechanism by Which Cancer Cells Inhibit Anti-tumor Immune Responses Revealed

Cancer cells are not just a group of cells that are out of control; for their own survival, they actively participate in the struggle with the immune system. Being able to evade detection by the immune system is a feature of cancer. In a new study, researchers from the University of Pennsylvania found that cancer cells release biological “unmanned aerial vehicles” – small vesicles called exosomes that circulate in the blood. These small vesicles carry the PD-L1 protein, which causes T cells to be exhausted before reaching the tumor – to help with this fight. Although the study focused on metastatic melanoma, these researchers found that breast cancer and lung cancer also release exosomes carrying PD-L1. The results of the study were published online in Nature, entitled “Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response”. The author of the paper is Dr. Wei Guo, a professor of biology at the University of Pennsylvania School of Arts and Sciences, and Dr. Xiaowei Xu, a professor of pathology and laboratory medicine at the Perelman School of Medicine at the University of Pennsylvania.

 

The study demonstrated how cancer can adopt a systematic approach to suppressing the immune system in a way that subverts existing ideas. In addition, it points to a new way to predict which cancer patients will respond to anti-PD1 therapy by destroying immunosuppression against tumors and provide a way to track the effects of such treatments.

 

 

“For many patients with metastatic melanoma, immunotherapy can save lives,” says Guo, “but about 70% of these patients don’t respond. These treatments are expensive and have toxic side effects, so knowing which patients will respond will be helpful. Identifying biomarkers in the blood may help predict which patients will respond, and may then provide a way for patients and their physicians to monitor treatment outcomes.”

 

Xu said, “Exosomes are tiny lipid-encapsulated vesicles that are less than 1/100 the diameter of red blood cells. The findings we have made in these circulating exosomes are indeed very remarkable. We have collected from acceptance blood samples from melanoma patients treated with anti-PD1 therapy. This liquid biopsy allows us to monitor tumor-associated immunosuppression over time.”

 

One of the most successful innovations in cancer treatment is the use of immune checkpoint inhibitor, which is designed to prevent cancer cells from suppressing the immune system and allowing tumors to thrive and spread. One of the main targets of such drugs is PD-1, a protein located on the surface of T cells. On the surface of tumor cells, they express a corresponding molecule called PD-L1, which interacts with the PD-1 protein on the surface of T cells, effectively shutting down the anti-cancer response of T cells. Blocking this interaction with an immune checkpoint inhibitor reactivates T cells, allows them to release the ability to kill cancer cells in the tumor.

 

Although cancer cells are known to carry PD-L1 on their surface, in this new study, these researchers found that exosomes from human melanoma cells also carry PD-L1 on their surface. The exosomes PD-L1 bind directly to T cells and inhibit the function of these T cells. The identification of exocytic PD-L1 secreted by tumor cells provides a major update to the immune checkpoint mechanism and provides new insights into tumor immune evasion.

 

“In essence, exosomes secreted by melanoma cells are immunosuppressive,” Guo said. “We propose a model in which these exosomes are resistant to circulating T cells like drones, even before the T cells are close to the tumor.” Given that a single tumor cell is capable of secreting many copies of the exosomes, the interaction between the exosomes carrying the PD-L1 and the T cells provides a means to systemically and efficiently inhibit the anti-tumor immune response systemically. This may explain why the immune system of cancer patients may be weakened.

 

Given the circulation of exosomes in the blood, they provide a viable approach to monitoring cancer/T cell through blood tests compared to traditional methods that are more invasive tumor biopsies. After the acute treatment phase, these researchers envisioned a test method that monitors how well the drug controls cancer cells.

 

By measuring the level of PD-L1 before treatment, oncologists may be able to predict the patient’s tumor burden and correlate it with treatment outcomes. In addition, blood tests may measure the effectiveness of the treatment, such as PD-L1 levels in exosomes may indicate the level of activation of T cells by the immune checkpoint inhibitor.

 

Guo said, “In the future, I think we will start to treat cancer as a chronic disease, just like diabetes. Just as diabetics use blood glucose meters to measure blood glucose levels, monitoring PD-L1 and other biomarkers on circulating exosomes may be a way for clinicians and cancer patients to pay close attention to treatment. This is another step towards achieving the goal of precision medicine and personalized medicine.”

 

 

Reference

Gang Chen, Alexander C. Huang, Wei Zhang et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature, Published Online: 08 August 2018, doi:10.1038/s41586-018-0392-8.

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