Increasing evidence demonstrates the immune system plays an intimate and complicated role in tumorigenesis. In theory, damaged neoplastic cells differentially express molecules that act as signals to the immune system, triggering pathways resulting in clearance. There are many ligands and receptors implicated in these interactions, including the well-studied TLRs and their cytosolic PRR counterparts, NLRs, which will be the focus of this project. Several recent studies have shown that mice lacking NLRs and downstream caspase effector molecules are much more susceptible to neoplastic transformation in mouse models of colitis-associated colorectal cancer. Furthermore, our laboratory has recently shown that artificial expression of the TLR and NLR agonist flagellin within tumor cells prevented their growth once implanted into recipient mice (Garaude et al., Science Translational Medicine, 2012). Thus it appears that NLRs have an endogenous role in controlling aberrant cell proliferation and transformation in inflammatory settings, and manipulation of NLR signaling can greatly enhance immune protection against tumor development. The role of NLRs in immune responses is an area of intense inquiry, with many questions still remaining. Most groups examine IL-1 and IL-18 cytokine production after inflammasome engagement, but none have studied the role of the inflammasome pathway in antigen presentation and adaptive immune activation. Here we will look at two members of this family of receptors, NLRC4 (also known as IPAF) and NAIP5, which are known to synergize with ASC for pro-inflammatory signaling in response to flagellin. We had demonstrated that engagement of this NLR pathway was essential for initiation of an anti-tumor adaptive response and memory, but the specific roles of these two molecules in recognition and adaptive immune activation after flagellin administration are still unclear. The goal of this study is thus twofold- 1) to understand the constituents, their contributions, and the downstream consequences of the NLRC4/NAIP5/ASC immune pathway in the context of tumor cells, and 2) to examine the potential for therapeutic exploitation of this pathway in a model of cancer vaccination. Our main approach will be to implant flagellin expressing tumor cells into recipient mice lacking components of the NLRC4/NAIP5 pathway, and to examine the in vivo impact on tumor development of these specific immune impairments. Further vaccination studies with dying tumor cells and in vitro cell culture studies with cells derived from NLRC4, NAIP5, and ASC deficient mice will allow elucidation of the contribution of these molecules to activation of the adaptive immune system and memory responses. Once the activity of NLRs in the tumor setting is better understood, future studies could expand to develop better ways of manipulating their signaling to direct a more effective immune response against cancer.
The research proposed herein is intended to enhance our understanding of the immune system's interactions with cancer, and ways to exploit this interaction. This could have implications for the manner in which cancer cases are managed, and even lead to novel therapeutic strategies for treatment. Furthermore, the focus is on pathways thought to be essential in regulating immune responses in general, rather than those involved in one specific disease, thus the findings will potentially have applications to a wide variety of clinical scenarios.
| Kent, Andrew; Blander, J Magarian (2014) Nod-like receptors: key molecular switches in the conundrum of cancer. Front Immunol 5:185 |
