University of Minnesota Medical School researchers have uncovered a new way to potentially target and treat late-stage colorectal cancer by identifying a novel mechanism by which colorectal cancer cells evade an anti-tumour immune response, which helped them develop an exosome-based therapeutic strategy to potentially treat the disease.
"Late-stage colorectal cancer patients face enormous challenges with current treatment options. Most of the time, the patient's immune system cannot efficiently fight against tumours, even with the help of the FDA-approved cancer immunotherapies," said Dr Subree Subramanian, an associate professor in the U of M Medical School's Department of Surgery, and a senior author of the study.
In partnership with Dr Xianda Zhao, a postdoctoral fellow in Subramanian's laboratory, the duo set out to investigate how colorectal cancer becomes resistant to available immunotherapies. The findings were published in the paper, 'Tumour secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumour specific T-cell responses', was published in Gastroenterology.
Colorectal cancer cells secrete exosomes that carry immunosuppressive microRNAs (miR-424) that actually prevent T cell and dendritic cell function because they block key proteins (CD28 and CD80) on these immune cell types, respectively. In the absence of these proteins, the T cells, which would normally kill the cancer cells, become ineffective and are eliminated from tumours, allowing tumours to grow.
By blocking these immunosuppressive microRNAs in cancer cells, the team observed an enhanced anti-tumour immune response and discovered that cancer cell-secreted exosomes also contain tumour-specific antigens that can stimulate the tumour-specific T cell response.
The researchers tested tumour-secreted exosomes without immunosuppressive microRNAs, in combination with immune checkpoint inhibitors, as a novel combination therapy in preclinical models with advanced-stage colorectal cancer, which proved effective.
"Our studies indicate that disrupting specific immunosuppressive factors in tumour cells helps unleash the immune system to effectively control tumour growth and metastasis in preclinical models with late-stage colorectal cancer," said Subramanian, who is also a member of the Masonic Cancer Center. "Eliminating the immune suppressive effects of those exosomes is now the focus of a new treatment option for patients with this deadly disease."
The intellectual property behind the modified exosome technology has been protected with assistance from the U of M Technology Commercialization. The team is currently developing clinical-grade exosomes that can be tested in clinical trials for patients with colorectal cancer.