Radiation therapy, when combined with immune checkpoint inhibitors, can be a promising treatment for non-small cell lung cancer (NSCLC). Why the two together have had success is not well understood. Now, a team from Weill Cornell Medicine has identified a specific dose of radiation therapy that had success when combined with immune checkpoint inhibitors. Not only that, they showed that the immune-modulating functions of radiation therapy are due to the activation of Scgb1a1+ club cells in the lung.

The researchers showed, in a mouse model of lung cancer, that these club cell factors inhibit highly potent immunosuppressive cells called myeloid-derived suppressor cells (MDSCs), which tumors often recruit to help them evade antitumor immune responses. The inhibition of the MDSCs led to an increase in the number of antitumor T cells at the tumor site, and greatly improved the effectiveness of FDA approved PD1 immunotherapy. These new findings, of an immunoregulatory role of club cells, have the potential to guide future clinical trials of immune checkpoint inhibitors in NSCLC.

This work is published in Nature Cancer in the paper, “Radiation-activated secretory proteins of Scgb1a1+ club cells increase the efficacy of immune checkpoint blockade in lung cancer.

“These club cell-secreted factors are able to nullify immune suppressor cells that otherwise help tumors escape an effective antitumor response,” said Vivek Mittal, PhD, professor of cell and developmental biology in cardiothoracic surgery at Weill Cornell Medicine. “We’re excited by the possibility of developing these club cell factors into a cancer treatment.”

Using a mouse model of NSCLC, the most common form of lung cancer, Mittal and colleagues first established that the immune-enhancing effect peaked at a moderate dose of radiation, and caused the quadrupling, to 40%, of the proportion of immune checkpoint inhibitor-treated mice who survived tumor-free to the end of the two-month observation period.

The researchers then found that radiation has this effect by activating and stimulating the proliferation of lung-resident club cells, which are known to help protect and repair sensitive airway linings, in part by reducing inflammation.

“It’s possible that we see a peak stimulation of these cells at a particular radiation dose because a lower dose doesn’t stress the cells enough, whereas a higher dose kills them,” said Nasser Altorki, MD, professor of cardiothoracic surgery at Weill Cornell Medicine.

The activated club cells secrete various molecules, and the researchers found that they could replace the radiation with a “club cocktail” of eight of these molecules and get essentially the same immune checkpoint inhibitor-enhancing result.

They also determined that this immune-restoring effect of the club cell molecules stems from their inhibition of MDSCs—which have long been seen as an obstacle to the improved efficacy of cancer immunotherapies.

To confirm the relevance of these laboratory findings to human cancers, the researchers looked at blood serum samples from lung cancer patients in a clinical trial of radiotherapy plus immune checkpoint inhibitor, conducted recently by Altorki and colleagues at Weill Cornell Medicine. They observed that levels of a key club cocktail molecule, CC10, were significantly elevated in most (5 of 8) of the patients who improved following the treatment, but in none (0 of 9) of the patients who failed to improve—hinting that CC10 can help patients improve.

The researchers are currently working to determine which of the molecules in their club cocktail are most important for inhibiting MDSCs and enhancing cancer treatments. They also plan to investigate whether these club cell molecules can inhibit MDSCs in other tumor contexts.

“We hope that these secreted molecules will be able to enhance treatments not just for non-small cell lung cancer patients but for patients with other cancers as well,” said Dingcheng Gao, PhD, associate professor of cell and developmental biology in cardiothoracic surgery at Weill Cornell Medicine. “These molecules may also be useful as biomarkers predicting the response to combined radiotherapy and immunotherapy.”

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