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Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer
Radhashree Maitra1, Titto Augustine1, Yitzchak Dayan1
1Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA.
Abstract:
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.
Insights
New research shows that blocking Toll Like Receptor 3 (TLR3) enhances reovirus
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Metastatic colorectal cancer (mCRC) requires novel therapies, particularly for KRAS-mutated tumors unresponsive to anti-EGFR treatments.
- Reovirus, a double-stranded RNA virus, is being investigated for chemotherapy-refractory KRAS-mutated mCRC.
- Toll Like Receptor 3 (TLR3) recognizes double-stranded RNA viruses like reovirus as part of the innate immune system.
Purpose of the Study:
- To investigate the role of TLR3 in reovirus detection and its impact on KRAS-mutated colorectal cancer.
- To evaluate the potential of modulating TLR3 expression to enhance reovirus efficacy against KRAS-mutated mCRC.
Main Methods:
- Utilized TLR3-expressing HEK-Blue™-hTLR3 cells to confirm TLR3 as the reovirus recognition motif.
- Investigated TLR3's effect on reovirus infection in KRAS-mutated HCT116 cells.
- Employed siRNA to downregulate TLR3 expression and assessed reovirus' anticancer activity in vitro and in vivo xenograft models.
Main Results:
- Confirmed TLR3 as the host pattern recognition receptor for reovirus.
- Demonstrated that high TLR3 expression in KRAS-mutated cells dampens reovirus infection via innate immune response.
- Showed that TLR3 downregulation using siRNA enhances reovirus' anticancer efficacy and tumor response rates in vivo.
Conclusions:
- TLR3 plays a critical role in the host's response to reovirus infection in KRAS-mutated colorectal cancer.
- Downregulating TLR3 can potentiate reovirus as a therapeutic agent against KRAS-mutated mCRC.
- Targeting the TLR3 pathway offers a strategy to improve reovirus efficacy for KRAS-mutated CRC.