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Credit: Paul Biris\/Getty Images<\/p>\n Credit: Paul Biris\/Getty Images<\/p>\n
Bone metastases in cancer patients resist immune checkpoint blockade<\/a> (ICB) therapies by hijacking key immune cells and converting them into agents of immune suppression, according to a new study by researchers from the Ludwig Collaborative Laboratory at Weill Cornell Medicine and Nanjing University. The study, published in Cancer Cell<\/a>, identifies immature neutrophils that are reprogrammed by the DKK1 protein as central players in creating an immunosuppressive state in the tumor microenvironment that helps promote metastatic tumor growth.<\/p>\n \u201cThis study uncovers a key reason why immunotherapy often fails in patients with bone metastases,\u201d said study co-leader Taha Merghoub, PhD, deputy director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. \u201cThat 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.\u201d<\/p>\n Neutrophils are an important component of the innate immune system and were once thought to play mainly short-lived roles in fighting infection and inflammation. But emerging evidence in the past decade is finding that their role in cancer is far more complex. The current study looked to build on these findings, including earlier work by many of the same researchers, to better understand the role of neutrophils in suppressing immune response.<\/p>\n Bone is a frequent site of metastasis in advanced cancers, with rates ranging from 40% to 90% in lung, breast, and prostate cancers, and increasingly in gastrointestinal cancers. Bone metastases are currently incurable. While ICB therapies, including anti-PD-1 and anti-CTLA-4 agents, have been transformative in many primary tumors, they exhibit poor efficacy in bone metastases. The reasons for this disparity have been poorly understood.<\/p>\n \u201cWe aimed to address\u2026knowledge gaps by exploring the role, modulation, and functional pattern of immature neutrophils in the tumor immune microenvironment (TIME), especially in bone metastases,\u201d the researchers wrote.<\/p>\n The new research points to a molecule called Dickkopf-1 (DKK1), found in high levels in both mouse models and human bone metastases. DKK1 reprograms neutrophils into a functionally immature state marked by the suppression of cytotoxic (CD8+) T cells, which are critical to the efficacy of immunotherapies. In this dysfunctional state, neutrophils release CHI3L3, a protein that inhibits T cell activation and tumor-killing activity.<\/p>\n The research team then showed that DKK1 has strong potential as a therapeutic target to aid immunotherapies.<\/p>\n \u201cWe 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,\u201d said study co-leader Tao Shi, PhD, a postdoctoral researcher at Weill Cornell. \u201cThe 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\u2014specifically anti-PD-1 treatment\u2014started working effectively again, even eliminating tumors in some cases.\u201d<\/p>\n