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Cancer exports molecular 'saboteurs' to remotely disarm immune system

Christian Fernsby |
Immunotherapy drugs known as checkpoint inhibitors have revolutionized cancer treatment: many patients with malignancies that until recently would have been considered untreatable are experiencing long-term remissions.

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But the majority of patients don't respond to these drugs, and they work far better in some cancers than others, for reasons that have befuddled scientists.

Now, UC San Francisco researchers 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 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.

One reason that some tumors may be resistant to these treatments is that they do not produce PD-L1, meaning that there is nowhere for existing checkpoint inhibitors to act, that is, they may avoid the immune system using other checkpoint proteins yet to be discovered.

Scientists have previously shown the PD-L1 protein to be present at low levels, or completely absent, in tumor cells of prostate cancer patients, potentially explaining their resistance to the therapy.

But in their new paper Blelloch's group is suggesting a very different answer to this puzzle: PD-L1 is being mass-produced by these tumors, they found, but instead of displaying the protein on their surface, cancer cells export PD-L1 in molecular freighters known as exosomes.

These PD-L1-packed exosomes sprout from cancer cells and travel through the lymphatic system or bloodstream to lymph nodes, the sites where immune cells are activated to protect the body.

There, the PD-L1 proteins act as itinerant molecular saboteurs, remotely disarming immune cells and preventing them from locating tumors to mount an anti-cancer offensive.

So rather than shutting down the immune response at the tumor surface, exosomal PD-L1 can inhibit immune cells before they even arrive there.

And unlike PD-L1 found on the tumor's surface, exosomal PD-L1, for unclear reasons, is resistant to existing checkpoint inhibitors.

To show that exosomal PD-L1 was responsible for imparting immune invisibility, the researchers turned to a mouse prostate cancer model that's resistant to checkpoint inhibitors.

When they transplanted these cancer cells into healthy mice, tumors rapidly sprouted.

But when the scientists used the gene-editing tool CRISPR to delete two genes required for exosome production, the edited cancer cells were unable to form tumors in genetically identical mice.

Though both edited and unedited cells were producing PD-L1, only those unable to create exosomes were visible and vulnerable to the immune system when PD-L1 was blocked.

In a complementary experiment, the same CRISPR-edited cancer cells were transplanted into healthy mice, immediately followed by a series of injections of exosomes carrying PD-L1.

Unable to produce exosomes, the CRISPR-edited cancer cells should have fallen victim to the immune system.

Instead, the injected exosomes were able to neutralize the immune response on behalf of the cancer, which allowed the exosome-deficient cancer cells to form tumors.

To figure out how exosomal PD-L1 was interfering with the immune system, the researchers inspected the lymph nodes of mice that received either CRISPR-edited or unadulterated cancer cells.

Mice that received the edited cells showed increased immune cell proliferation and had higher numbers of activated immune cells in their lymph nodes, the central command hubs of the immune system.

In a separate mouse model, a colorectal cancer that's only partially responsive to immunotherapy, the researchers identified two distinct pools of PD-L1: one on the surface of tumor cells that's sensitive to PD-L1 inhibitors, and another in exosomes that's resistant.

When they treated the cancer with a combination therapy that involved both preventing exosome formation and administering PD-L1 inhibitors, the mice survived longer than those treated with either approach alone.


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