Toll-like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer
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Radhashree Maitra1, Titto Augustine1, Yitzchak Dayan1, Carol Chandy1, Matthew Coffey2 and Sanjay Goel1
1Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA
2Oncolytics Biotech Inc., Calgary, AB T2N 1X7, Canada
Sanjay Goel, email: firstname.lastname@example.org
Keywords: Toll-like receptor, reovirus, colorectal cancer, innate immunity, immunotarget
Received: August 29, 2016 Accepted: March 10, 2017 Published: April 04, 2017
New therapeutic interventions are essential for improved management of patients with metastatic colorectal cancer (mCRC). This is especially critical for those patients whose tumors harbor a mutation in the KRAS oncogene (40-45% of all patients). This patient cohort is excluded from receiving anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients. Reovirus, a double stranded (ds) RNA virus is in clinical development for patients with chemotherapy refractory KRAS mutated tumors. Toll Like Receptor (TLR) 3, a member of the toll like receptor family of the host innate immune system is the pattern recognition motif for dsRNA pathogens. Using TLR3 expressing commercial HEK-BlueTM-hTLR3 cells we confirm that TLR3 is the host pattern recognition motif responsible for the detection of reovirus. Further, our investigation with KRAS mutated HCT116 cell line showed that effective expression of host TLR3 dampens the infection potential of reovirus by mounting a robust innate immune response. Down regulation of TLR3 expression with siRNA improves the anticancer activity of reovirus. In vivo experiments using human CRC cells derived xenografts in athymic mice further demonstrate the beneficial effects of TLR3 knock down by improving tumor response rates to reovirus. Strategies to mitigate the TLR3 response pathway can be utilized as a tool towards improved reovirus efficacy to specifically target the dissemination of KRAS mutated CRC.
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