Pancreatic tumors use clotting pathway to build immune shields, study finds
Researchers at the Icahn School of Medicine at Mount Sinai have found that small populations of pancreatic cancer cells can create localized immune-protective niches that shield tumors from immune attack. The finding could open new avenues for making immunotherapy more effective against one of the deadliest forms of cancer.
Researchers at the Icahn School of Medicine at Mount Sinai have discovered that isolated pancreatic cancer cells can form localized, immune-protective zones around tumors, hindering their response to immunotherapy. This study, published in Nature, reveals that a select population of pancreatic cancer cells activate genes that stabilize fibrin, a protein involved in blood clotting and wound healing.
By utilizing this mechanism, the cancer cells create a protective environment that hinders immune cells, such as T cells, from accessing the tumor. Disrupting this protective mechanism in preclinical models led to a reduction in tumor growth and enhanced responses to immunotherapy, indicating a potential strategy to overcome pancreatic cancer's resistance to immune-based treatments.
Pancreatic cancer remains one of the most challenging cancers to treat due to its exceptional ability to evade the immune system. The study, conducted using advanced spatial genomics technology called Perturb-map, identified two proteins—PAI1 and PAI2—as key drivers of immune protection. These proteins promote fibrin buildup, attracting and retaining macrophages that prevent the infiltration of cancer-fighting immune cells into the tumor.
The findings demonstrate that immune suppression does not occur uniformly throughout the tumor but rather exists in small, localized niches created by a minority of cancer cells. By selectively targeting these niches through genetic removal or pathway-blocking drugs, researchers observed improvements in immune activation, reduced tumor growth, and enhanced effectiveness of anti-PD-1 immunotherapy.
This discovery opens up new avenues for therapeutic interventions, potentially combining these approaches with existing immunotherapies to improve treatment outcomes for patients with pancreatic cancer. The research also highlights the connection between the clotting system, wound healing, and macrophage control in various diseases, including aging and neurodegenerative disorders, suggesting broader therapeutic applications beyond cancer treatment.
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