New RORC-Expressing Dendritic Cells Linked to Immune Tolerance in Metastatic Cancer
- Researchers at Mass General Brigham have discovered a rare population of RORC-expressing dendritic cells within malignant ascites, fluid that accumulates in the abdominal cavity of advanced cancer patients.
- The work was co-led by Steven Blum, MD, and jointly supervised by Gary Reynolds, MD, PhD, Samuel Klempner, MD, and Alexandra-Chloé Villani, PhD, at the Krantz Family Center...
- While malignant ascites is often viewed simply as a late-stage complication, the multiomic analysis showed it operates as a distinct and highly organized immune environment.
Researchers at Mass General Brigham have discovered a rare population of RORC-expressing dendritic cells within malignant ascites, fluid that accumulates in the abdominal cavity of advanced cancer patients. Published in Science Immunology under the title Multiomic analysis of malignant ascites defines RORC-expressing dendritic cells at sites of metastasis, the study examines how these cells may foster an immune-tolerant environment around metastatic cancer.
Study Details and Multiomic Methods Used in Ascites Analysis
The work was co-led by Steven Blum, MD, and jointly supervised by Gary Reynolds, MD, PhD, Samuel Klempner, MD, and Alexandra-Chloé Villani, PhD, at the Krantz Family Center for Cancer Research within the Mass General Brigham Cancer Institute and the Mass General Brigham Center for Immunology & Inflammatory Diseases. Investigators collected ascites and blood specimens directly from patients with stomach and esophagus cancers. They built a primary dataset containing more than 500,000 cells by combining single-cell RNA sequencing, cell-surface protein measurements, immune-receptor sequencing, and profiling of soluble proteins in blood and ascites.
Discovery of RORC-Expressing Dendritic Cells in Metastatic Patients
While malignant ascites is often viewed simply as a late-stage complication, the multiomic analysis showed it operates as a distinct and highly organized immune environment. The most notable finding was a rare population of dendritic cells expressing the gene RORC, termed RORC DCs. Although these cells formed a very small fraction of immune cells, investigators detected them in 22 of the 23 patients in the initial cohort. The research team noted that these cells resemble a family of immune cells recently discovered in mice and humans that helps establish immune tolerance, which prevents the immune system from attacking harmless substances or the body’s own tissues.
Therapeutic Implications for Advanced Solid Tumors
Roughly one in ten patients with advanced solid tumors develop malignant ascites, a condition associated with poor responses to chemotherapy and immunotherapy and particularly common in gastric and gastroesophageal cancers. The identification of RORC DCs suggests that cancer exploits normal mechanisms of immune tolerance to make T cells less effective at attacking tumors. Investigators found signals in the ascites environment that can be targeted with existing drugs, which could potentially be re-positioned and given directly into the abdominal cavity.
Future Evaluation of Metastatic Cancer Pathways
The findings do not change clinical care today, but they establish pathways and potential therapeutic targets that researchers are currently evaluating in patient-derived models. Investigators aim to understand the origin and activity of RORC DCs to determine whether their behavior can be modified to strengthen anti-cancer immunity in future clinical trials.