Immunotherapy-Resistant Tumors Export PD-L1-Packed Exosomes That Travel to Lymph Nodes to Remotely Inhibit Immune Cell Activation; Understanding Biology of Exosomal PD-L1 May Be First Step Toward Novel Therapies

Immunotherapy drugs known as checkpoint inhibitors have recently revolutionized cancer treatment: many patients with malignancies that, until recently, would have been considered untreatable are experiencing long-term remissions. But the majority of patients do not respond to these drugs, and they work far better in some cancers than others, for reasons that have befuddled scientists. Now, researchers at the University of California, San Francisco (UCSF), and a collaborator at UC Berkeley, have identified a surprising phenomenon that may explain why many cancers don’t respond to these drugs, and hints at new strategies to unleash the immune system against disease. “In the best-case scenarios, like melanoma, only 20 to 30 percent of patients respond to immune checkpoint inhibitors, while in other cases, like prostate cancer, there is only a single-digit response rate,” said Robert Blelloch (, MD, PhD, Professor of Urology at UCSF and senior author of the new study, published online on April 4, 2019 in Cell. “That means a majority of patients are not responding. We wanted to know why.” In malignant tissue, a protein called PD-L1 functions as an “invisibility cloak”: by displaying PD-L1 on their surfaces, cancer cells protect themselves from attacks by the immune system. Some of the most successful immunotherapies work by interfering with PD-L1 or with its receptor, PD-1, which resides on immune cells. When the interaction between PD-L1 and PD-1 is blocked, tumors lose their ability to hide from the immune system and become vulnerable to anti-cancer immune attacks.
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