The innate immune response is the first line of defense against the threat of invading pathogens, as well as the development of cellular transformation, with the latter ultimately leading to cancer. Two major players in innate immunity are the lipid antigen presenting CD1d molecules, and the immunoregulatory NKT cells that recognize them. Evidence from multiple laboratories suggests that NKT cells can regulate adaptive immunity, thus serving as a bridge between the innate and adaptive immune responses. From the perspective of a CD1d+ tumor, being able to prevent NKT cell recognition would thus thwart overall antitumor immunity. Multiple myeloma (MM) is a devastating disease, with patients surviving from a few months to at most several years following diagnosis. Even with new treatments emerging, MM is still incurable. Thus, it is important to understand, at a fundamental level, the characteristics of MM cells that permit it to persist in a host. Recent evidence has suggested that NKT cell responses in MM patients are impaired and that MM cells express surface CD1d molecules. Additional work has shown that cell signaling pathways contribute to MM cell survival, metastasis and immune evasion. The ability of a blood tumor cell to avoid recognition by the host's antitumor immunosurveillance system is an obstacle to treatments that can prevent (or control) the development of systemic tumor. We and others have shown that the innate immune response, specifically, CD1d-mediated lipid antigen presentation to NKT cells, is an important component of the antitumor immune response against blood cancers. Recently, we have demonstrated that several signal transduction pathways regulate antigen presentation by CD1d, as well as by MHC class II molecules. It is known that a variety of tumors alter these cell signaling pathways. The overall goal of this application is to understand in more detail the mechanisms by which CD1d-mediated antigen presentation is regulated normally and how CD1d+ myeloma tumor cells are impaired in their ability to present antigen to NKT cells. Our hypothesis is that ROCK negatively regulates CD1d-mediated antigen presentation by two means: 1. Control of actin polymerization and 2. Activation of JNK, which reduces antigen presentation by CD1d, independently of the actin cytoskeleton. To test this hypothesis, the following specific aims are proposed: 1. Dissect in detail the mechanism(s) by which the ROCK pathway regulates antigen presentation by CD1d to NKT cells;2. Determine the role of the ROCK pathway in controlling CD1d-mediated antigen presentation in human multiple myeloma cells;3. Analyze the role of the ROCK pathway in the antitumor immune response by NKT cells in vivo. Increasing our understanding of the molecular mechanisms that govern antigen presentation by CD1d has applications not only in cancer, but also in infectious diseases, vaccine development and autoimmune diseases.
This project will investigate how human multiple myeloma (blood cancer) cells are able to evade recognition by the immune system. We are focused specifically on changes in the intracellular scaffold (cytoskeleton) of these cancer cells and what controls these changes. Increasing our understanding of immune evasion by tumors has important applications not only to cancer, but also to autoimmunity and infectious diseases as well.
