DKK1 identified as key driver of immune resistance in bone metastases

Many major cancers, including those of the lung, breast and prostate gland, spread to the bones as they progress. These bone metastases are often debilitating, even deadly. They are also notoriously resistant to all kinds of treatment, including immunotherapy.

Now a Ludwig Cancer Research study has identified in the microenvironment of bone tumors a key architect of that resistance. Researchers co-led by Taha Merghoub and Tao Shi of the Ludwig Collaborative Laboratory at Weill Cornell Medicine with colleagues at Nanjing University in China have discovered that frontline soldiers of the immune system known as neutrophils are reprogrammed in bone metastases into a functionally immature state in which they suppress anti-tumor immune responses.

That reprogramming, they report in the current issue of Cancer Cell, is accomplished by a protein churned out by bone metastases known as DKK1. Shi, Merghoub and colleagues show that DKK1 blockade restores the sensitivity of bone metastases to cancer immunotherapy in mouse models of cancer.

This study uncovers a key reason why immunotherapy often fails in patients with bone metastases. That failure is caused by the accumulation within the metastases of large numbers of immature, immunosuppressive neutrophils induced by DKK1 that cultivate a profoundly immunosuppressive tumor microenvironment."

Taha Merghoub, Ludwig Collaborative Laboratory at Weill Cornell Medicine

Neutrophils are critical agents of the innate immune system, the body's frontline defense against pathogens. Like other innate immune cells, such as macrophages, they play complex and highly mutable roles in cancer depending on their functional states.

Their abundance in tumors has, on the one hand, long been associated with poor patient prognosis. Along those lines, a recent study-co-led by Merghoub and Shi with a couple of the same colleagues in China-identified a specific class of immature neutrophil precursors as potent suppressors of anti-tumor immune responses and promoters of cancer progression across multiple tumor types.

On the other hand, neutrophils in other functional states can be key supporters of anti-tumor immunity. Merghoub and his colleagues have previously shown, for example, that they are essential to the complete destruction of advanced melanoma and colorectal tumors in mouse models during immunotherapy. (Ludwig Lausanne researchers reported analogous findings in mouse models of lung and colon cancer around the same time.)

Shi, Merghoub and colleagues show in the current study that distinct, functionally immature neutrophils associated with bone metastases produce another molecule, CHI3L3, that disrupts the activation and function of cytotoxic (CD8+) T cells. Solders of the adaptive immune system, CD8+ T cells are the immune system's primary killers of cancer cells and the main cell type engaged by immune checkpoint blockade therapies.

The elevated levels of DKK1 seen in mouse models were echoed in analyses of patient data and in serum samples obtained from gastric cancer patients with bone metastases. In experiments using cultured cells and mouse models, the researchers also identified the biochemical signaling cascade activated by DKK1 that reprograms neutrophils into an immature state, identifying several potential drug targets to disrupt the process.

"We tested what would happen if we blocked the effects of DKK1 in mice with bone metastases of triple-negative breast cancer using an antibody to the molecule," said Shi. "The results were dramatic. Neutrophils matured into a healthier and more helpful form in which they stopped producing CHI3L3 and no longer suppressed cytotoxic T cell function. As a result, bone tumors shrank and immune checkpoint blockade immunotherapy-specifically anti-PD-1 treatment-started working effectively again, even eliminating tumors in some cases."

These findings suggest that DKK1-blockade could be used as a combination treatment to improve the efficacy of immune checkpoint blockade therapies against bone tumors, for which there are no currently effective therapies.

"This is an exciting possibility, especially since a DKK1-blocking antibody (DKN-01) is already in clinical trials," said Shi. "That could significantly hasten progress in translating these findings into patient care."

Beyond that, CHI3L3-as well as the signature of gene expression it triggers-could serve as biomarkers to identify patients with high neutrophil-mediated immune suppression and better tailor treatments to their tumors.

In more general terms, the authors say, their study highlights the importance of targeting and reprogramming innate immune cells like neutrophils-not just T cells-for cancer therapy.