Bone Metastases Promote Immature Immune Cells That Hamper Immunotherapy Effectiveness

Bone metastases from cancers such as lung, breast, and prostate are common as these cancers progress and often lead to severe health complications or death. These metastatic tumors in the bone are known for their resistance to various treatments, including immunotherapy, making management particularly challenging. Recent research by Ludwig Cancer Research has uncovered a key mechanism behind this resistance. Researchers, led by Taha Merghoub and Tao Shi from the Ludwig Collaborative Laboratory at Weill Cornell Medicine, in collaboration with colleagues at Nanjing University, have found that within the bone tumor microenvironment, immune system cells called neutrophils are reprogrammed into an immature and immunosuppressive state by a protein known as DKK1 produced by bone metastases. This reprogramming causes neutrophils to suppress anti-tumor immune responses, creating a tumor-friendly environment that impedes effective immunotherapy.

The study, published in Cancer Cell, highlights how the accumulation of these immature neutrophils is a major factor in the failure of immunotherapies in patients with bone metastases. Interestingly, these neutrophils produce a molecule called CHI3L3 that hampers the activity of cytotoxic CD8+ T cells—true immune system soldiers responsible for attacking cancer cells. Elevated levels of DKK1 were observed not only in mouse models but also in patients, including serum samples from gastric cancer patients with bone metastases. Blocking DKK1 in experiments helped revert neutrophils to a healthier state, thereby restoring the immune system's ability to fight the tumors.

This reprogramming and suppression mechanism suggests that combining DKK1 inhibitors with existing immunotherapies could significantly improve treatment outcomes for bone metastatic cancers—a promising development considering a DKK1-blocking antibody, DKN-01, is already undergoing clinical trials. Moreover, molecules like CHI3L3 and specific gene signatures may serve as biomarkers to identify patients likely to benefit from targeted therapies. Overall, this research emphasizes the importance of targeting innate immune cells like neutrophils in cancer therapy, expanding the focus beyond T cells alone, to overcome resistance and improve patient prognosis.