Club cell factors may reverse immune suppression in tumours

Researchers at Cornell University, US, have identified a set of anti-immunosuppressive factors that can be secreted by club cells that line airways in the lungs and showed how these club cell factors inhibit myeloid-derived suppressor cells (MDSCs) in mouse models. The team hope to develop their findings into a future cancer therapy.

In recent decades, researchers have set out to find ways to harness the immune system against cancers. That effort has yielded treatments such as immune checkpoint inhibitors (ICIs) which partly undo tumours’ immunosuppressive effects. Oncologists also have observed that ionising radiation, a standard treatment for many cancers, can further undo this immune suppression and thereby enhance the effectiveness of ICI treatments.

In this new study, the team investigated how radiation has this immune-enhancing effect. Using a mouse model of non-small-cell lung carcinoma, the most common form of lung cancer, they first established that this effect peaked at a moderate dose of radiation and caused the quadrupling, to 40 percent, of the proportion of ICI-treated mice who survived tumour-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 is possible that we see a peak stimulation of these cells at a particular radiation dose because a lower dose does not stress the cells enough, whereas a higher dose kills them,” posited co-senior author Dr Nasser Altorki.

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 obtain the same ICI-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 team looked at blood serum sampled from lung cancer patients in a clinical trial of radiotherapy plus ICI. They observed that levels of a key club cocktail molecule, CC10, were significantly elevated in most of the patients who improved following the treatment, but in none of the patients who failed to improve, suggesting that CC10 can help patients improve.

The researchers are now 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 tumour 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,” added Dr Dingcheng Gao, one of the authors of the study. “These molecules may also be useful as biomarkers predicting the response to combined radiotherapy and immunotherapy.”

The study was published in Nature Cancer.