Elucidating the Role of Pattern Recognition Receptors in Understanding, Treating, and Targeting Cancer
Scaia, Veronica Marie
MetadataShow full item record
Pattern Recognition Receptors (PRRs) are a group of evolutionarily conserved and germline-encoded cellular receptors of the innate immune system that are responsible for recognizing and responding to the entirety of the pathogens a host encounters. The ingenuity of the innate immune system is that with a comparatively miniscule pool of receptors, these receptors are capable of responding to a diverse and large array of pathogens and damage signals. Two highly relevant subsets of PRRs include nucleotide binding domain leucine rich repeat containing (NOD-like) receptors (NLRs) and Toll-like receptors (TLRs). Both NLRs and TLRs have been implicated in several diseases, including autoimmune disorders, inflammatory conditions, and cancer. Mice lacking a specific NLR, NLRP1, are more susceptible to chemically induced colitis and colitis-associated tumorigenesis. We investigated whether the absence of NLRP1 in the gastrointestinal tract influenced the composition of the microbiome, and whether it was responsible for the predisposition of these animals to colitis-associated cancer. By carefully controlling for non-genotype influences, we found that in fact maternal and housing factors were greater predictors over genotype of gut flora composition. This study concluded with a clearer understanding of NLRP1. We next investigated the effectiveness of a novel tumor ablation therapy, termed High-Frequency Irreversible Electroporation (H-FIRE) in a murine model of triple negative breast cancer. The chosen 4T1 model closely mimics aggressive human metastatic triple negative breast cancer, and metastasizes to the same organs. After ablation of the primary mammary tumor, we saw significant improvements in disease burden and metastases, both of which were accompanied by PRR activation within the tumor microenvironment, implicating PRRs in the successful treatment outcome following H-FIRE ablation. Lastly, we generated novel CRISPR-Cas9 plasmids to genetically manipulate the Tlr4 gene of wild type C57Bl/6 mice in order to recapitulate the LPS-hyporesponsive TLR4 protein of C3H/HeJ mice. This proof-of-concept study successfully demonstrated that PRRs can be targets for gene editing purposes, and that nanoparticle delivery leads to enhanced and improved delivery. Collectively, this work attempts to better appreciate the role of PRRs in understanding, treating, and targeting cancer.
- Doctoral Dissertations