How one common immune cell prevents checkpoint inhibitors from attacking cancer

This lung sample from a patient who did not respond to checkpoint inhibitors shows how T cells (blue) are trapped, while the neutrophils (purple) are widespread among the cancer cells, shown in white and gray. (Fred Hutchinson Cancer Research Institute)

Checkpoint inhibitors like Merck’s Keytruda are lifesaving for some cancer patients but ineffective for others, and figuring out the differences between responders and non-responders has proven challenging. Now, scientists at the Fred Hutchinson Cancer Research Center believe they’ve found a culprit for the lack of response to checkpoint inhibition—and it’s a common cell that’s prevalent in the human bloodstream.

Immune cells known as neutrophils can flood into tumors, outnumbering cancer-fighting T cells and dampening the response to checkpoint inhibitors, the Fred Hutch team discovered. When they used a drug to decrease the population of neutrophils in mouse models of non-small cell lung cancer (NSCLC), they were able to improve the animals’ responses to checkpoint inhibition, they reported in the journal JCI Insight.

The researchers were clued into the overabundance of neutrophils in checkpoint inhibition non-responders after they analyzed tumor samples from 28 NSCLC patients. They proved out their theory in mice by administering anti-PD1 drugs along with an investigational drug from Syntrix Pharmaceuticals that lowers the amount of neutrophils in and around tumors.

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A clinical trial of the Syntrix drug, called SX-682, in combination with Keytruda was recently initiated in patients with melanoma. The Fred Hutch team is currently seeking grants to start its own clinical studies, according to a statement.

RELATED: What causes immuno-oncology drug resistance? 2 research teams uncover clues

Establishing a proper balance of neutrophils and T cells is just one of many ideas being investigated for boosting immuno-oncology drugs. Over the summer, University of Colorado researchers published early evidence that HDAC inhibitors could improve responses to PD-1 blockers, though Syndax Pharmaceuticals has so far struggled to show positive results in studies of its HDAC inhibitor with Keytruda.

The University of Colorado also contributed to a study showing that a combination of Bristol-Myers Squibb’s blood cancer drug Sprycel with anti-PD-1 therapy was effective in mouse models of multiple tumor types. BMS is now testing its PD-1 blocker Opdivo with Sprycel in NSCLC.

The Fred Hutch study didn’t determine exactly how neutrophils interfere with PD-1 inhibition, but scientists have long been aware that the cells can suppress T cells. The Fred Hutch team is looking for other molecular markers they hope can be used someday to predict which patients will best respond to immunotherapy—and which drugs or combination treatments will be most likely to benefit them.

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