Scientists found a rare subset of senescent macrophages that shields tumors behind a fibrotic barrier from the immune system, and used nanoparticles to neutralize them, giving two clinically failed drugs a second chance
Scientists found a rare subset of senescent macrophages that shields tumors behind a fibrotic barrier from the immune system, and used nanoparticles to neutralize them, giving two clinically failed drugs a second chance
On September 24, Science published a study from Scott Lowe's laboratory at Memorial Sloan Kettering Cancer Center. The team identified a subpopulation of senescent macrophages bearing P-selectin on their surface that maintains scar tissue around liver and lung tumors. The researchers loaded two clinically failed drugs into nanoparticles made of fucoidan, which binds P-selectin, and delivered them selectively to these cells. In mice, this removed fibrosis without the toxicity of the free drugs and restored the tumors' sensitivity to immunotherapy. The same nanoparticle also killed its target in tumors from cancer patients.
Liver and lung tumors grow in organs scarred by chronic inflammation, whether from hepatitis or cirrhosis. The scar walls the tumor off from immune cells and suppresses the few that do infiltrate, which is why immunotherapy (a treatment that releases the brakes on immune cells and directs them to attack the tumor) is largely ineffective in these settings.
Hinterleitner, Barthe, Goldberg, and colleagues set out to find which cells in the scar tissue are responsible. In their paper in Science, they describe a rare subset of macrophages (scavenger cells of the immune system that engulf pathogens). These cells carry P-selectin, a marker of inflamed tissue, and have entered senescence: they no longer divide but emit signals that recruit collagen into the scar and suppress neighboring immune cells.
"By sending out these signals, these cells build a wall that prevents the immune system from doing its job"says co-author Valentin Barthe in an MSK press release. These cells account for only 3–5% of fibrotic tissue, but removing them sharply reduces fibrosis.
Two years earlier, a separate genetic experiment in mice had shown that removing this subset of senescent macrophages caused liver fibrosis to regress, unlike clearance of p16-positive liver cells, which induced it. But the marker used in that experiment, the p16 protein, sits inside the cell where a drug cannot reach it from outside. Guiding a nanoparticle requires a surface marker, and P-selectin proved to be one. Navitoclax killed these cells and dBET6 silenced their signals. Both worked in mice but failed in clinical trials because they hit senescent cells throughout the body, causing platelet depletion. The delivery solution came from an adjacent project: Daniel Heller had built a fucoidan nanoparticle that binds P-selectin to ferry drugs across the blood-brain barrier.
"Our nanoparticles do not take out just any macrophage. They target precisely the narrow subset that drives fibrosis"explains bioengineer Heller, who designed the platform.
In mice, the nanoparticles cleared liver and lung fibrosis as effectively as the free drugs but without causing platelet depletion: blood counts and survival stayed normal. In tumors growing in fibrotic organs (as they do in humans), the nanoparticle modestly slowed growth on its own, and combined with immunotherapy it produced durable regression. When CD8+ T cells (the immune system's killer cells) were depleted, the effect nearly vanished: the immune system is what kills the tumor, and the nanoparticle merely opens the door.
The same subset was found in tumors from patients with liver and lung cancer. The more of these cells present, the greater the fibrosis and the less likely a response to immunotherapy. Among 19 lung cancer patients assessed before surgery, non-responders had more of these cells. In tumor samples from three lung cancer patients, the nanoparticle killed this subset without affecting other cells.
Targeted delivery has restored the rationale for two drugs abandoned because of toxicity. MSK is seeking partners for clinical trials.