Cancer Cells Can Flood Bloodstream with Protein ‘Warriors’ Against Immune Response, Study Finds

Cancer Cells Can Flood Bloodstream with Protein ‘Warriors’ Against Immune Response, Study Finds

Cancer cells release into the bloodstream small vesicles armed with PD-1 ligand (PD-L1) — a protein that suppresses the activation of cancer-fighting immune cells — so as to mute anti-tumor immunity throughout the body, researchers report.

Study results also showed that vesicle-associated PD-L1 in the blood may work as a treatment response biomarker, helping to distinguish patients most likely respond to anti-PD-L1 therapies.

The study, “Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response,” was published in the journal Nature.

A well-known and powerful mechanism of immune evasion by cancer cells is the presence of PD-L1 on their cell surface, which will bind to its PD-1 receptor on T-cells to prevent the activation of T-cells — a type of white blood cell that fights cancer.

Previous studies have also shown that the presence of PD-L1 on cancer cells’ surface can increase in response to the release of interferon gamma (IFN-γ) — a protein with anti-cancer properties — by activated T-cells.

Several approved anti-cancer therapies target and block this interaction (PD-L1 with its PD-1 receptor) to promote T-cell activation and stimulate anti-canter immune responses. However, many patients with PD-L1-producing cancers do not respond to these therapies.

A collaboration between researchers — those at the University of Pennsylvania, Wuhan University, Xi’an Jiaotong University, Wistar Institute, University of Texas, and Mayo Clinic — sheds light on the immune-evasion mechanisms of cancer and possible causes behind the non-response to therapies.

The researchers found that human melanoma cells not only have PD-L1 on their surface, but they also release into the bloodstream large amounts of small vesicles — called exosomes — with PD-L1 on their surface, which systemically suppress anti-cancer immune responses. This finding was also true for breast and lung cancer cells.

In a mouse model of melanoma, injections of PD-L1-vesicles promoted tumor growth and led to a significantly lower number of T-cells able to infiltrated tumor cells and the lymph nodes. The addition of antibodies against PD-L1 strongly suppressed those effects.

These findings supported that exosomal PD-L1 systemically suppresses anti-tumor immunity, but this effect can be prevented or reduced with PD-L1/PD-1 blockade-based therapies.

Analysis of exosomal PD-L1 levels in melanoma patients prior to starting Keytruda (pembrolizumab) — an anti-PD-1 therapy — revealed that those who failed to respond to Keytruda treatment had significantly higher baseline levels of exosomal PD-L1.

Patients who responded to Keytruda showed a greater increase in exosomal PD-L1 level as early as three to six weeks following treatment start, which the researchers suggested may reflect the cancer’s response to the re-activation of T-cells and their production of the cancer-fighting protein IFN-γ.

But this response will have no lasting, damaging effects, because the interaction between PD-L1 and PD-1 is blocked by Keytruda.

High baseline (pre-treatment) levels of exosomal PD-L1 in patients who fail to respond to treatment “may reflect the ‘exhaustion’ of T cells to a stage at which they can no longer be reinvigorated by anti-PD-1 treatment,” the team wrote.

This non-response, researchers suggested, may be due to an impaired T-cell response or to the development of a resistance mechanism to IFN-γ by cancer cells.

These results also suggest that blood levels of exosomal PD-L1 may be used to predict which patients are more likely to respond to PD-L1/PD-1 blockade therapies, and to monitor treatment response.

“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,” Guo Wei, a professor of biology at the University of Pennsylvania, said in a Xinhua news release.

This would represent a more accessible and less invasive way of monitoring the battle between T-cells and cancer, compared to traditional tumor biopsy.