Zhu (MMSc-IMM) Studies On DNA Mismatch Repair Pathway In Colorectal Cancer

Despite medical advances in treatment strategies over the past years, colorectal cancer (CRC) remains one of the most prevalent cancers in the US with a high mortality rate. Locally advanced and metastatic CRC have poor prognoses and only a small subset (5- 15%) of patients have tumors with DNA mismatch repair (MMR) deficiency responding to immunotherapy. The low tumor infiltrating lymphocytes remains the major obstacle hindering the efficacy of most immunotherapies in CRC treatment. To enhance tumor neoantigen production and provoke robust inflammatory multicellular network within tumor, we designed an EpCAM AsiC aptamer system knocking down the Mlh1 gene in tumor to convert MMR-proficient (pMMR) CRC to a MMR-deficient phenotype and hence make resistant pMMR sensitive to immune checkpoint blockade. The results from this study support evidence that the MLH1 AsiC binds to EpCAM+ CRC cell lines and induces tumor-specific MLH1 downregulation with no significant toxicity. Mice that received the MLH1 AsiC treatment were also found to have decreased tumor growth and enhanced survival, offering a promising alternative to expand the range of CRC tumors that respond to immunotherapies.