A rare type of immune cell may help metastatic cancer evade the body’s defenses, according to research published in Science Immunology. Scientists from the Mass General Brigham Cancer Institute and the Center for Immunology & Inflammatory Diseases examined fluid from abdominal cavities in late-stage cancer patients—malignant ascites—and uncovered a previously unrecognized group of dendritic cells associated with immune tolerance.
The study focuses on RORC-expressing dendritic cells (RORC DCs), detected in 22 of 23 patients with advanced solid tumors. Though scarce, these cells appear to suppress immune responses against cancer, potentially explaining why some patients do not respond to immunotherapy. The lead authors, Steven Blum, MD; Gary Reynolds, MD, PhD; Samuel Klempner, MD; and Alexandra-Chloé Villani, PhD, describe ascites as a “distinct and highly organized immune environment” that might be addressed with existing medications.
Malignant ascites occurs when cancer spreads to the abdomen, causing fluid accumulation that often requires repeated drainage. Roughly one in ten patients with advanced solid tumors develop it, particularly those with gastric or gastroesophageal cancers, whose survival drops to just months once ascites appears. Current treatments primarily relieve symptoms rather than addressing the underlying immune mechanisms. This research suggests ascites is not merely a disease byproduct but an active factor in how cancer manipulates immunity.
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How cancer cells hijack immune tolerance
The researchers used single-cell RNA sequencing and protein profiling to analyze over 500,000 cells from ascites samples, isolating RORC DCs for further investigation. These cells resemble a recently identified immune population in mice and humans known for promoting tolerance, preventing autoimmune attacks. In cancer, however, this tolerance may instead shield tumors from T-cell responses.
While the findings do not immediately translate to clinical practice, they highlight why some metastatic cancers resist treatment. The team is now testing whether blocking RORC DCs or their signaling pathways could restore immune function in patient-derived models.
The discovery also raises questions about how cancer exploits normal immune regulation. In healthy tissue, tolerance prevents autoimmunity, but in metastasis, it may inadvertently protect tumors.
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RORC DCs found across multiple metastatic cancers
The researchers expanded their analysis beyond gastric and gastroesophageal cancers to determine whether RORC DCs appeared in ascites from other metastatic sites. Using the same single-cell sequencing methods, they studied fluid samples from patients with ovarian, colorectal, and pancreatic cancers, all of which frequently involve abdominal metastasis. In each case, the rare dendritic cells were present, though their prevalence varied. This pattern across tumor types suggests RORC DCs may represent a broader mechanism by which metastatic cancers suppress immune surveillance, rather than a localized issue tied to specific cancers.
To trace the origin of these cells, the team isolated RORC DCs from primary tumors and lymph nodes in separate experiments. Protein profiling revealed they produce signaling molecules that recruit other immune-suppressive cells, creating a feedback loop that reinforces tolerance. One key molecule, a cytokine that dampens T-cell activity, was found at higher concentrations in ascites where RORC DCs were abundant. The authors noted this cytokine is already targeted by approved therapies for autoimmune diseases, suggesting potential repurposing in cancer treatment.
The study’s most immediate clinical implication involves redirecting existing therapies. Early results showed that inhibiting the cytokine pathway weakened the cells’ ability to suppress immune responses, though further validation is required.